Oxazine derivatives

ABSTRACT

The present invention provides, for example, a compound mentioned below as a medicament for treating or preventing the diseases induced by production, secretion or deposition of amyloid-β proteins. 
     A compound of the formula (I): 
                         
wherein R 1 , R 2a , R 2b , R 3 , R 4a , R 4b , ring A and the dashed lines are defined in the specification,
 
its pharmaceutically acceptable salt or a solvate thereof.

TECHNICAL FIELD

The present invention relates to a compound which has amyloid βproduction inhibitory activity, and is useful as an agent for treatingor preventing disease induced by production, secretion and/or depositionof amyloid β proteins.

BACKGROUND ART

In the brain of Alzheimer's patient, the peptide composed of about 40amino acids residue as is called amyloid β protein, that accumulates toform insoluble specks (senile specks) outside nerve cells is widelyobserved. It is concerned that these senile specks kill nerve cells tocause Alzheimer's disease, so the therapeutic agents for Alzheimer'sdisease, such as decomposition agents of amyloid β protein and amyloidvaccine, are under investigation.

Secretase is an enzyme which cleaves a protein called amyloid βprecursor protein (APP) in cell and produces amyloid β protein. Theenzyme which controls the production of N terminus of amyloid β proteinis called as β-secretase (beta-site APP-cleaving enzyme 1, BACE1). It isthought that inhibition of this enzyme leads to reduction of producingamyloid β protein and that the therapeutic or prophylactic agent forAlzheimer's disease will be created due to the inhibition.

Patent Documents 1 to 11 disclose compounds having a structure similarto those of the compounds of the present invention. Each of thesedocument discloses each of these compound is useful as a therapeuticagent for Alzheimer's disease or Alzheimer's relating symptoms, but eachof these substantially disclosed compounds has a structure differentfrom those of the compounds of the present invention. Non PatentDocument 1 disclose compounds having a structure similar to those of thecompounds of the present invention but does not suggest anypharmacological activities.

PRIOR ART Patent Document

-   [Patent Document 1] WO2007/058583 pamphlet-   [Patent Document 2] WO2007/049532 pamphlet-   [Patent Document 3] WO2008/133273 pamphlet-   [Patent Document 4] WO2008/133274 pamphlet-   [Patent Document 5] WO20. 09/151098 pamphlet-   [Patent Document 6] WO2009/091016 pamphlet-   [Patent Document 7] WO2009/103626 pamphlet-   [Patent Document 8] WO2009/134617 pamphlet-   [Patent Document 9] WO2006/065277 pamphlet-   [Patent Document 10] WO2005/58311 pamphlet-   [Patent Document 11] WO2008/103351 pamphlet

Non-Patent Document

-   [Non-patent Document 1] Russian Journal of Organic Chemistry (2003),    39 (12), 1789-1791

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention provides compounds which have reducing effects toproduce amyloid β protein, especially BACE1 inhibitory activity, and areuseful as an agent for treating disease induced by production, secretionand/or deposition of amyloid β protein.

Means for Solving the Problem

The present invention, for example, provides the inventions described inthe following items.

(1) A compound of formula (I):

whereinring A is a substituted carbocycle or a substituted or unsubstitutedheterocycle,R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,

wherein R^(za) and R^(zb) are each independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclylalkyl,substituted or unsubstituted carbocyclylalkoxy, substituted orunsubstituted carbocyclyloxycarbonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy or substituted or unsubstitutedheterocyclyloxycarbonyl, or R^(za) and R^(zb) together with the carbonatom to which they are attached may form a substituted or unsubstitutednon-aromatic carbocycle or a substituted or unsubstituted non-aromaticheterocycle,R^(3a), R^(3b), R^(3c), R^(4a), R^(4b) and R^(4c) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl,R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,ring Q is a substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle,dashed line a, dashed line b and dashed line c each independently meanthe presence or absence of a bond,when dashed line a means the presence of a bond, then R^(3b) and R^(4b)are absent,when dashed line b means the presence of a bond, then R^(3c) is absent,when dashed line c means the presence of a bond, then R^(4c) is absent,Y¹ and Y² are each independently —C(R⁵)(R⁶)—, —C(R⁵)═, —N(R⁷)—, —N═,—S—, —SO—, —SO₂ or —O—,Y³ and Y⁴ are each independently —C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—, —SO₂—or —O—,R⁵ and R⁶ are each independently hydrogen, halogen, hydroxy, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkenylthio, substituted or unsubstitutedalkynylthio, substituted or unsubstituted acyl, substituted orunsubstituted acyloxy, cyano, nitro, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, andR⁷ is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted amino, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclylalkyl,substituted or unsubstituted carbocyclylalkoxy, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heterocyclylalkoxy, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, excluding the compounds wherein

ring A is

-   -   wherein ring A′ and ring B are each independently a substituted        or unsubstituted carbocycle or a substituted or unsubstituted        heterocycle,    -   Z is -L^(1′)-N(R⁸)-L^(2′)-,    -   L^(1′) and L^(2′) are each independently a bond;    -   substituted or unsubstituted alkylene wherein the substituent is        one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino,        hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxyalkyl carbamoyl, sulfamoyl, alkylsulfamoyl,        alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino,        alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino,        alkylsulfinylimino, cyano, nitro, a carbocyclic group and a        heterocyclic group, each of which carbocycle and heterocycle is        optionally substituted by one or more substituent selected from        halogen, alkyl, hydroxy and alkoxy;    -   substituted or unsubstituted alkenylene wherein the substituent        is one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxy        imino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxy alkylcarbamoyl, sulfamoyl, alkylsulfamoyl,        alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino,        alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino,        alkylsulfinylimino, cyano, nitro, a carbocyclic group and a        heterocyclic group, each of which carbocycle and heterocycle is        optionally substituted by one or more substituent selected from        halogen, alkyl, hydroxy and alkoxy; or    -   substituted or unsubstituted alkynylene wherein the substituent        is one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino,        hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,        alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino,        alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino,        cyano, nitro, a carbocyclic group and a heterocyclic group, each        of which carbocycle and heterocycle is optionally substituted by        one or more substituent selected from halogen, alkyl, hydroxy        and alkoxy; and    -   R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted        or unsubstituted alkenyl, substituted or unsubstituted alkynyl        or substituted or unsubstituted acyl,        its pharmaceutically acceptable salt or a solvate thereof.        When Z is “-L^(1′)-N(R⁸)-L^(2′)-”, then “L^(1′)” bonds to ring B        and “L^(2′)” bonds to ring A′, respectively.        (1-1) A compound of the formula (Iα):

whereinring A is a substituted carbocycle or a substituted or unsubstitutedheterocycle,R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,

wherein R^(2a) and R^(2b) are each independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, or substituted or unsubstitutedheterocyclyloxycarbonyl, or R^(za) and R^(zb) together with the carbonatom to which they are attached may form a substituted or unsubstitutednon-aromatic carbocycle or a substituted or unsubstituted non-aromaticheterocycle,R^(3a), R^(3b), R^(3c), R^(4a), R^(4b) and R^(4c) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl,R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,ring Q is a substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle,dashed line a, dashed line b and dashed line c each independently meanthe presence or absence of a bond,when dashed line a means the presence of a bond, then R^(3b) and R^(4b)are absent,when dashed line b means the presence of a bond, then R^(3c) is absent,when dashed line c means the presence of a bond, then R^(4c) is absent,Y¹ and Y² are each independently —C(R⁵)(R⁶)—, —C(R⁵)═, —N(R⁷)—, —N═,—S—, —SO—, —SO₂— or —O—,Y³ and Y⁴ are each independently —C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—, —SO₂—or —O—,R⁵ and R⁶ are each independently hydrogen, halogen, hydroxy, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkenylthio, substituted or unsubstitutedalkynylthio, substituted or unsubstituted acyl, substituted orunsubstituted acyloxy, cyano, nitro, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl, andR⁷ is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted amino, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, excluding the compounds wherein

ring A is

-   -   wherein ring A′ and ring B are each independently a substituted        or unsubstituted carbocycle or a substituted or unsubstituted        heterocycle,    -   Z is -L¹′-N(R⁸)-L²′-,    -   L¹′ and L²′ are each independently a bond;    -   substituted or unsubstituted alkylene wherein the substituent is        one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino,        hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,        alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino,        alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino,        cyano, nitro, a carbocyclic group and a heterocyclic group, each        of which carbocycle and heterocycle is optionally substituted by        one or more substituent selected from halogen, alkyl, hydroxy        and alkoxy;    -   substituted or unsubstituted alkenylene wherein the substituent        is one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino,        hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,        alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino,        alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino,        cyano, nitro, a carbocyclic group and a heterocyclic group, each        of which carbocycle and heterocycle is optionally substituted by        one or more substituent selected from halogen, alkyl, hydroxy        and alkoxy; or    -   substituted or unsubstituted alkynylene wherein the substituent        is one or more selected from halogen, alkoxy, halogenoalkoxy,        hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy,        alkoxycarbonyl, amino, acylamino, alkylamino, imino,        hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,        hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,        alkylsulfonylamino, alkylsulfofiylalkylamino,        alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino,        alkylsulfinylimino, cyano, nitro, a carbocyclic group and a        heterocyclic group, each of which carbocycle and heterocycle is        optionally substituted by one or more substituent selected from        halogen, alkyl, hydroxy and alkoxy; and    -   R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted        or unsubstituted alkenyl, substituted or unsubstituted alkynyl        or substituted or unsubstituted acyl,        its pharmaceutically acceptable salt or a solvate thereof.        When Z is “-L¹-N(R⁸)-L²-”, then “L¹” bonds to ring B and “L²”        bonds to ring A′, respectively.        (1-2) A compound of the type (Iα):

whereinring A is a substituted carbocycle or a substituted or unsubstitutedheterocycle,R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,

wherein R^(za) and R^(zb) are each independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, or substituted or unsubstitutedheterocyclyloxycarbonyl, or R^(za) and R^(zb) together with the carbonatom to which they are attached may form a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle,R^(3a), R^(3b), R^(3c), R^(4a), R^(4b) and R^(4c) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl,R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,ring Q is a substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle,dashed line a, dashed line b and dashed line c each independently meanthe presence or absence of a bond,when dashed line a means the presence of a bond, then R^(3b) and R^(4b)are absent,when dashed line b means the presence of a bond, then R^(3c) is absent,when dashed line c means the presence of a bond, then R^(4c) is absent,Y¹ and Y² are each independently —C(R⁵)(R⁶)—, —C(R⁵)═, —N(R⁷)—, —S—,—SO—, —SO₂— or —O—,Y³ and Y⁴ are each independently —C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—, —SO₂—or —O—,R⁵ and R⁶ are each independently hydrogen, halogen, hydroxy, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkenylthio, substituted or unsubstitutedalkynylthio, substituted or unsubstituted acyl, substituted orunsubstituted acyloxy, cyano, nitro, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl, andR⁷ is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted amino, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, excluding the compounds wherein

ring A is

-   -   wherein ring A′ and ring B are each independently a substituted        or unsubstituted carbocycle or a substituted or unsubstituted        heterocycle,    -   Z is -L¹-N(R⁸)-L²-,    -   L¹ and L² are each independently a bond, substituted or        unsubstituted alkylene, substituted or unsubstituted alkenylene        or substituted or unsubstituted alkynylene; and    -   R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted        or unsubstituted alkenyl, substituted or unsubstituted alkynyl        or substituted or unsubstituted acyl,        its pharmaceutically acceptable salt or a solvate thereof.        When Z is “-L¹-N(R⁸)-L²-”, then “L¹” bonds to ring B and “L²”        bonds to ring A′, respectively.        (2) The compound according to any one of items (1), (1-1), and        (1-2) wherein ring A is

wherein ring A′ and ring B are each independently a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,Z is -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or -L¹-N(R⁸)-L²-,L¹ and L² are each independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted alkenylene or substituted orunsubstituted alkynylene andR⁸ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,its pharmaceutically acceptable salt or a solvate thereof.When Z is “-L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²-, or -L¹-N(R⁸)-L²-”,“L¹” bonds to ring B and “L²” bonds to ring A′, respectively.(3)

The compound according to any one of items (1), (1-1), (1-2), and (2)wherein

wherein R^(za) and R^(zb) are each independently hydrogen, halogen orsubstituted or unsubstituted alkyl, and R^(4a) and R^(4b) are eachindependently hydrogen or substituted or unsubstituted alkyl,its pharmaceutically acceptable salt or a solvate thereof.(4)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein R^(3a), R^(3b), R^(4a) and R^(4b) are the same as defined initem (1),its pharmaceutically acceptable salt or a solvate thereof.(5-1)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein R^(3a) and R^(4a) are the same as defined in item (1),its pharmaceutically acceptable salt or a solvate thereof.(5-2)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein Y¹ and Y² are each independently —C(R⁵)═ or —N═, and Q is thesame as defined in item (1),its pharmaceutically acceptable salt, or solvate thereof.(5-3)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein Y¹ is —C(R⁵)═ or —N═, Y² is —C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—,—SO₂— or —O—, and Qand R^(4c) are the same as defined in item (1),its pharmaceutically acceptable salt, or solvate thereof.(5-4)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein Y¹—C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—, —SO2-, or —O—, Y² is —C(R⁵)═or —N═, and Q andR^(3c) are the same as defined in item (1),its pharmaceutically acceptable salt, or solvate thereof.(5-5)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein Q, Y¹ and Y² are each independently —C(R⁵)(R⁶)—, —N(R⁷)—, —S—,—SO—, —SO₂—, or —O—,R^(3c) and R^(4c) are the same as defined in item (1), itspharmaceutically acceptable salt, or solvate thereof.(5-6)

The compound according to any one of items (1), (1-1), (1-2) and (2)wherein

wherein Q, Y³ and Y⁴ are the same as defined in item (1), itspharmaceutically acceptable salt, or solvate thereof.(6) The compound according to any one of items (2) to (4) and (5-1) to(5-6) wherein —Z— is —C(═O)N(R⁸)—, its pharmaceutically acceptable saltor a solvate thereof.(7) The compound according to any one of items (2) to (4), (5-1) to(5-6) and (6) wherein ring A′ is substituted or unsubstituted benzene,and ring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazine, itspharmaceutically acceptable salt or a solvate thereof.(8) The compound according to any one of items (1), (1-1), (1-2), (2) to(4), (6) and (7) wherein R^(4a) and R^(4b) are both hydrogen, itspharmaceutically acceptable salt or a solvate thereof.(9) The compound according to any one of items (1), (1-1), (1-2), (2) to(4), (5-1) to (5-6) and (6) to (8) wherein R¹ is C1 to C3 unsubstitutedalkyl, its pharmaceutically acceptable salt or a solvate thereof.(10) The compound according to any one of items (1), (1-1), (1-2), (2)to (4), (5-1) to (5-6) and (6) to (9) wherein R^(2a) and R^(2b) are bothhydrogen, its pharmaceutically acceptable salt or a solvate thereof.(11) A pharmaceutical composition comprising the compound according toany one of items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6)to (10), its pharmaceutically acceptable salt or a solvate thereof as anactive ingredient.(12) A pharmaceutical composition having BACE1 inhibitory activitycomprising the compound according to any one of items (1), (1-1), (1-2),(2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt or a solvate thereof as an active ingredient.(13) A method for inhibiting BACE1 activity comprising administering thecompound according to any one of items (1), (1-1), (1-2), (2) to (4),(5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt ora solvate thereof.(14) The compound according to any one of items (1), (1-1), (1-2), (2)to (4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptablesalt or a solvate thereof for use in a method for inhibiting BACE1activity.(15) Use of a compound according to any one of items (1), (1-1), (1-2),(2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt, or solvate thereof for manufacturing a medicament forinhibiting BACE1 activity.(16) A method for treating or preventing diseases induced by production,secretion or deposition of amyloid β proteins comprising administeringthe compound according to any one of items (1), (1-1), (1-2), (2) to(4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptablesalt or a solvate thereof.(17) Use of a compound according to any one of items (1), (1-1), (1-2),(2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt, or solvate thereof for manufacturing a medicament fortreating or preventing diseases induced by production, secretion ordeposition of amyloid β proteins.(18) A compound according to any one of items (1), (1-1), (1-2), (2) to(4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptablesalt, or solvate thereof for use in treating or preventing diseasesinduced by production, secretion or deposition of amyloid β proteins.(19) A method for treating or preventing Alzheimer's disease comprisingadministering the compound according to any one of items (1), (1-1),(1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt, or solvate thereof.(20) Use of a compound according to any one of items (1), (1-1), (1.2),(2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt or solvate thereof for manufacturing a medicament fortreating or preventing Alzheimer's disease.(21) A compound according to any one of items (1), (1-1), (1.2), (2) to(4), (5-1) to (5-6) and (6) to (10), its pharmaceutically acceptablesalt or solvate thereof for use in treating or preventing Alzheimer'sdisease.(22) A method, a system, an apparatus, a kit or the like formanufacturing the compound according to any one of items (1), (1-1),(1-2), (2) to (4), (5-1) to (5-6) and (6) to (10), its pharmaceuticallyacceptable salt or a solvate thereof.(23) A method, a system, an apparatus, a kit or the like for preparing apharmaceutical composition comprising the compound according to any oneof items (1), (1-1), (1-2), (2) to (4), (5-1) to (5-6) and (6) to (10),its pharmaceutically acceptable salt or a solvate thereof.(24) A method, a system, an apparatus, a kit or the like for use thecompound according to any one of items (1), (1-1), (1-2), (2) to (4),(5-1) to (5-6) and (6) to (10), its pharmaceutically acceptable salt ora solvate thereof.(25) A pharmaceutical composition according to item (11) or (12) fortreating or preventing a disease induced by production, secretion ordeposition of amyloid β proteins.(26) A pharmaceutical composition according to item (11) or (12) fortreating or preventing Alzheimer's disease.

Effect of the Invention

The compound of the present invention is useful as an agent for treatingor preventing disease induced by production, secretion or deposition ofamyloid β proteins such as Alzheimer's disease.

MODE FOR CARRYING OUT THE INVENTION

In the specification, the “halogen” includes fluorine, chlorine,bromine, and iodine.

In the specification, the “alkyl” includes linear or branched alkyl of acarbon number of 1 to 15, for example, a carbon number of 1 to 10, forexample, a carbon number of 1 to 6, and for example, a carbon number of1 to 3. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl,isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.

The alkyl portions in “alkoxy”, “halogenoalkyl”, “hydroxyalkyl”,“halogenoalkoxy”, “hydroxy alkoxy”, “alkoxycarbonyl”,“halogenoalkoxycarbonyl”, “alkylamino”, “aminoalkyl”, “alkoxyalkoxy”,“alkoxyalkenyloxy”, “alkoxyalkynyl”, “alkylcarbonyl”, “alkylcarbamoyl”,“hydroxyalkylcarbamoyl”, “alkoxyimino”, “alkylthio”, “alkylsulfonyl”,“alkylsulfonylamino”, “alkylsulfonylalkylamino”, “alkylsulfonylimino”,“alkylsulfinylamino”, “alkylsulfinylalkylamino”, “alkylsulfinylimino”,“alkylsulfamoyl”, “alkylsulfinyl”, “carbocyclylalkyl”,“carbocyclylalkoxy”, “carbocyclylalkoxycarbonyl”,“carbocyclylalkylamino”, “carbocyclylalkylcarbamoyl”, “cycloalkylalkyl”,“cycloalkylalkoxy”, “cycloalkylalkylamino”, “cycloalkylalkoxycarbonyl”,“cycloalkylalkylcarbamoyl”, “arylalkyl”, “arylalkoxy”, “arylalkylamino”,“arylalkoxycarbonyl”, “arylalkylcarbamoyl”, “heterocyclylalkyl”,“heterocyclylalkoxy”, “heterocyclylalkylamino”,“heterocyclylalkoxycarbonyl” and “heterocyclylalkylcarbamoyl” are thesame as the above “alkyl.”

“Substituted or unsubstituted alkyl” may be substituted with one or moresubstituents selected from a substituent group α.

As used herein, the substituent group α is a group consisting ofhalogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy,acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino,imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino,alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano,nitro, a carbocyclic group and a heterocyclic group, each of whichcarbocycle and heterocycle is optionally substituted with one or moresubstituent selected from halogen, alkyl, hydroxy, and alkoxy.

Examples of the substituents of “substituted or unsubstituted alkoxy”,“substituted or unsubstituted alkoxycarbonyl”, “substituted orunsubstituted alkylthio”, “substituted or unsubstituted alkylsulfonyl”and “substituted or unsubstituted alkylsulfinyl” are one or moreselected from the above-mentioned substituent group α.

Examples of “halogenoalkyl” are trifluoromethyl, fluoromethyl andtrichloromethyl.

Examples of “halogenoalkoxy” are trifluoromethoxy, fluoromethoxy,trichloromethoxy.

The term “alkylidene” includes a divalent group of the above “alkyl” andexamples are methylidene, ethylidene, propylidene, isopropylidene,butylidene, pentylidene and hexylidene.

The term “alkenyl” includes linear or branched alkenyl of a carbonnumber or 2 to 15, for example, a carbon number of 2 to 10, for example,a carbon number of 2 to 6, and for example, a carbon number of 2 to 4,having one or more double bonds at any available positions. Examplesinclude vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl and pentadecenyl.

The alkenyl portions in “alkenyloxy”, “alkenyloxycarbonyl”,“alkenylcarbonyl”, “alkoxyalkenyloxy”, “alkenylthio”, “alkenylamino”,“alkenylsulfonyl” and “alkenylsulfinyl” are the same as the above“alkenyl.”

The term “alkynyl” includes a linear or branched alkynyl of a carbonnumber of 2 to 10, preferably a carbon number of 2 to 8, furtherpreferably a carbon number of 3 to 6 having one or more triple bonds atoptionally positions. Examples include ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. These mayhave further a double bond at any available position.

Alkynyl portions in “alkoxyalkynyl”, “alkynyloxy”, “alkynyloxycarbonyl”,“alkynylcarbonyl”, “alkoxyalkynyloxy”, “alkynylthio”, “alkynylsulfinyl”,“alkynylsulfonyl” and “alkynylamino” are the same as the above“alkynyl.”

Examples of the substituent of “substituted or unsubstituted alkenyl”,“substituted or unsubstituted alkenyloxy”, “substituted or unsubstitutedalkenyloxycarbonyl”, “substituted or unsubstituted alkenylthio”,“substituted or unsubstituted alkenylsulfinyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkynyloxy”, “substituted or unsubstitutedalkynylthio”, “substituted or unsubstituted alkynyloxycarbony”,“substituted or unsubstituted alkynylsulfinyl” and “substituted orunsubstituted alkynylsulfonyl” are one or more substituent selected fromthe above-mentioned substituent group α.

Examples of the substituent in “substituted or unsubstituted amino”,“substituted or unsubstituted carbamoyl”, “substituted or unsubstitutedthiocarbamoyl” and “substituted or unsubstituted sulfamoyl” are one ortwo substituents selected from alkyl, acyl, hydroxy, alkoxy,alkoxycarbonyl, carbocyclic group and heterocyclic group.

The term “acyl” includes formyl, alkylcarbonyl of a carbon number of 1to 10, alkenylcarbonyl of a carbon number of 2 to 10, alkynylcarbonyl ofa carbon number of 2 to 10, carbocyclylcarbonyl andheterocyclylcarbonyl. Examples are formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl,methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl,furancarbonyl, thiophenecarbonyl, benzothiazolecarbonyl,pyrazinecarbonyl, piperidinecarbonyl and thiomorpholino.

The acyl portions in “acyloxy” and “acylamino” are the same as the above“acyl.”

Examples of the substituents of “substituted or unsubstituted acyl” and“substituted or unsubstituted acyloxy” are one or more substituentsselected from the substituent group α. The ring portions ofcarbocyclylcarbonyl and heterocyclylcarbonyl may be substituted with oneor more substituents selected from alkyl, substituent group α, and alkylsubstituted with one or more substituents selected from substituentgroup α.

The term “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl andnon-aromatic fused carbocyclyl.

The term “cycloalkyl” includes a carbocyclic group of a carbon number of3 to 10, for example, a carbon number of 3 to 8, and for example, acarbon number 4 to 8. Examples are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

The cycloalkyl portions in “cycloalkylalkyl”, “cycloalkyloxy”,“cycloalkylalkoxy”, “cycloalkylthio”, “cycloalkylamino”,“cycloalkylalkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”,“cycloalkylcarbamoyl”, “cycloalkylalkylcarbamoyl”,“cycloalkylalkoxycarbonyl” and “cycloalkyloxycarbonyl” are the same asthe above “cycloalkyl.”

The term “cycloalkenyl” includes a group having one or more double bondsat optionally positions in the ring of the above “cycloalkyl”. Examplesare cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl and cyclohexadienyl.

The term “aryl” includes phenyl, naphthyl, anthryl and phenanthryl.Specific example is phenyl.

The term “non-aromatic fused carbocyclic group” includes non-aromaticgroups wherein two or more cyclic groups selected from the above“cycloalkyl”, “cycloalkenyl” and “aryl” are fused. Examples are indanyl,indenyl, tetrahydronaphthyl and fluorenyl.

The carbocycle portions in “non-aromatic carbocycle” are the same as“cycloalkyl”, “cycloalkenyl” and “non-aromatic fused carbocyclic group.”Examples are cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene,cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

The carbocycle portions in “carbocycle”, “carbocyclyloxy”,“carbocyclylalkyl”, “carbocyclylalkoxy”, “carbocyclylalkoxycarbonyl”,“carbocyclylthio”, “carbocyclylamino”, “carbocyclylalkylamino”,“carbocyclylcarbonyl”, “carbocyclylsulfamoyl”, “carbocyclylsulfonyl”,“carbocyclylcarbamoyl”, “carbocyclylalkylcarbamoyl”,“carbocyclyloxycarbonyl”, “carbocyclylsulfinyl” and“carbocyclylsulfonyl” are the same as that of the above “carbocyclicgroup.”

The aryl portions in “arylalkyl”, “aryloxy”, “aryloxycarbonyl”,“arylalkoxycarbonyl”, “arylthio”, “arylamino”, “arylalkoxy”,“arylalkylamino”, “arylsulfonyl”, “arylsulfamoyl”, “arylcarbamoyl” and“arylalkylcarbamoyl” are the same as the above “aryl.”

The term “heterocyclic group” includes a heterocyclic group having oneor more hetero atoms optionally selected from O, S and N in a ring, andexamples include 5- to 6-membered heteroaryl such as pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl; non-aromaticheterocyclyl such as dioxanyl, thiiranyl, oxiranyl, oxetanyl,oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl,thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl,tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl,tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl,tetrahydrodiazepinyl and tetrahydropyridazinyl; fused bicyclicheterocyclyl such as indolyl, isoindolyl, indazolyl, indolizinyl,indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl,pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, furopyridyl,thienothienyl, imidazopyridyl, imidazopyrazolyl, pyrazolopyridyl,pyrazolopyrazinyl, thiazolopyridyl, pyrazolopyrimidinyl,pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxinyl, dihydrobenzoxezinyl, dihydrobenzodioxepinyl, anddihydrothienodioxinyl; fused tricyclic heterocyclyl such as carbazolyl,acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,dibenzofuryl, imidazoquinolyl, and tetrahydrocarbazolyl. Specificexamples are 5- or 6-membered heteroaryl and non-aromatic heterocyclyl.

The heterocycle portions in “heterocycle”, “heterocyclylalkyl”,“heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonyl”,“heterocyclylalkoxy”, “heterocyclylamino”, “heterocyclylsulfamoyl”,“heterocyclylsulfonyl”, “heterocyclylcarbamoyl”,“heterocyclyloxycarbonyl”, “heterocyclylalkylamino”,“heterocyclylalkoxycarbonyl”, “heterocyclylalkylcarbamoyl” and“heterocyclylsulfinyl” are the same as that of the above “heterocyclyl.”

The heterocycle portions of “non-aromatic heterocycle” are the same asthe heterocycle portion of the above “non-aromatic heterocyclyl.”Specific examples are dioxane, thiirane, oxirane, oxetane, oxathiolane,azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine,imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine,morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine,tetrahydrofuran, tetrahydropyran, dihydrothiazole, tetrahydrothiazole,tetrahydroisothiazole, dihydrooxazine, hexahydroazepine,tetrahydrodiazepine, and tetrahydropyridazine.

A bond of the above “heterocyclic group” may be situated on any ring.

The term “heteroaryl” includes an aromatic cyclic group among the“heterocyclic group”.

In the specification, examples of ring A are as follows:

wherein ring A′ and ring B are each independently substituted orunsubstituted carbocycle or substituted or unsubstituted heterocycle,L¹, L², and L³ are each independently a bond, substituted orunsubstituted alkynylene, substituted or unsubstituted alkenylene orsubstituted or unsubstituted alkynylene,═W¹ is ═O, ═S, or ═NR⁹,

W² is O, S, or N(R⁸),

R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,

R⁹ is hydrogen, hydroxy, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,

when ring A is (i), then the constituent carbon atom of L¹ and theconstituent carbon atom of L², or the constituent carbon atom of L¹ andthe nitrogen atom of W² may be connected with substituted orunsubstituted alkylene to form a ring,

when ring A is (ii), then the constituent carbon atom of L¹ and theconstituent carbon atom of L², or the nitrogen atom of W² and theconstituent carbon atom of L² may be connected with substituted orunsubstituted alkylene to form a ring,

when ring A is (iii), then two nitrogen atoms of W² may be connectedwith substituted or unsubstituted alkylene to form a ring,

when ring A is (vi), then the constituent carbon atom of L¹ and theconstituent carbon atom of L² may be connected by substituted orunsubstituted alkylene to form a ring, p is 1 or 2, and

when multiple L³, multiple W², or multiple R⁹ are present, each of themmay be independently different.

Specific examples are as follows:

wherein L is each independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted alkenylene or substituted orunsubstituted alkynylene, ring T is a carbocycle optionally substitutedwith a group(s) selected from the substituent group α, or a heterocycleoptionally substituted with a group(s) selected from the group α, andthat and other symbols are the same as defined above.

More specific examples are as follows:

wherein each symbol is the same as defined above.

wherein each symbol is the same as defined above.

Other examples of the substituent of “substituted carbocycle”,“substituted or unsubstituted carbocycle”, “substituted or unsubstitutedheterocycle”, “substituted or unsubstituted benzene”, “substituted orunsubstituted pyridine”, “substituted or unsubstituted pyrimidine”, and“substituted or unsubstituted pyrazine” in ring A, ring A′, and ring Binclude:

a group selected from the substituent group α such as halogen, hydroxy,alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano,alkylamino and/or alkylthio; alkyl substituted with one or more groupsselected from the substituent group α, hydroxyimino and alkoxyimino,wherein the substituent is, for example, halogen, hydroxy, alkoxy and/oralkoxycarbonyl, or unsubstituted alkyl;aminoalkyl substituted with one or more groups selected from thesubstituent group α;wherein the substituent is, for example, acyl, alkyl and/or alkoxy;alkenyl substituted with one or more substituents selected from thesubstituent group α, wherein the substituent is, for example,alkoxycarbonyl, halogen, and/or halogenoalkoxycarbonyl, or unsubstitutedalkenyl;alkynyl substituted with one or more substituents selected from thesubstituent group α, wherein the substituent is, for example,alkoxycarbonyl, or unsubstituted alkynyl;alkoxy substituted with one or more substituents selected from thesubstituent group α, wherein the substituent is, for example, halogen,carbamoyl, alkylcarbamoyl and/or hydroxyalkylcarbamoyl;alkoxyalkoxy substituted with one or more substituents selected from thesubstituent group α;alkenyloxy substituted with one or more substituents selected from thesubstituent group α, wherein the substituent is, for example, halogen,hydroxy, amino and/or alkylamino, or unsubstituted alkenyloxy;alkoxyalkenyloxy substituted with one or more substituents selected fromthe substituent group α; alkynyloxy substituted with one or moresubstituents selected from the substituentgroup α, wherein the substituent is, for example, halogen and/orhydroxy, or unsubstituted alkynyloxy;alkoxyalkynyloxy substituted with one or more groups selected from thesubstituent group α;alkylthio substituted with one or more substituents selected from thesubstituent group α, or unsubstituted alkylthio;alkenylthio substituted with one or more substituents selected from thesubstituent group α, or unsubstituted alkenylthio;alkynylthio substituted with one or more substituents selected from thesubstituent group α, or unsubstituted alkynylthio;alkylamino substituted with one or more substituents selected from thesubstituent group α;alkenylamino substituted with one or more substituents selected from thesubstituent group α;alkynylamino substituted with one or more substituents selected from thesubstituent group α;aminooxy substituted with one or more substituents selected from thesubstituent group α and alkylidene, or unsubstituted aminooxy;acyl substituted with one or more substituents selected from thesubstituent group α;alkylsulfonyl substituted with one or more substituents selected fromthe substituent group α, or unsubstituted alkylsulfonyl;alkylsulfinyl substituted with one or more substituents selected fromthe substituent group α, or unsubstituted alkylsulfinyl;alkylsulfamoyl substituted with one or more substituents selected fromthe substituent group α;a carbocyclic group such as cycloalkyl and aryl, substituted with one ormore substituents selected from the substituent group α, azide, alkyland halogenoalkyl;a heterocyclic group substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl;carbocyclylalkyl such as cycloalkylalkyl and arylalkyl, substituted withone or more substituents selected from the substituent group α, azide,alkyl and halogenoalkyl, or unsubstituted carbocyclylalkyl;heterocyclylalkyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylalkyl;carbocyclyloxy such as cycloalkyloxy and aryloxy, substituted with oneor more substituents selected from the substituent group α, azide, alkyland halogenoalkyl, or unsubstituted carbocyclyloxy;heterocyclyloxy substituted with one or more substituents selected fromthe substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclyloxy;carbocyclylalkoxy such as cycloalkylalkoxy and arylalkoxy, substitutedwith one or more substituents selected from the substituent group α,azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylalkoxy;heterocyclylalkoxy substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylalkoxy;carbocyclylalkoxycarbonyl such as cycloalkylalkoxycarbonyl andarylalkoxycarbonyl, substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted carbocyclylalkoxycarbonyl such as cycloalkylalkoxycarbonyland arylalkoxycarbonyl;heterocyclylalkoxycarbonyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkoxycarbonyl;carbocyclylthio such as cycloalkylthio and arylthio, substituted withone or more substituents selected from the substituent group α, azide,alkyl and halogenoalkyl, or unsubstituted carbocyclylthio such ascycloalkylthio and arylthio;heterocyclylthio substituted with one or more substituents selected fromthe substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylthio;carbocyclylamino such as cycloalkylamino and arylamino, substituted withone or more substituents selected from the substituent group α, azide,alkyl and halogenoalkyl, or unsubstituted carbocyclylamino such ascycloalkylamino and arylamino;heterocyclylamino substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylamino;carbocyclylalkylamino such as cycloalkylalkylamino and arylalkylamino,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl or unsubstitutedcarbocyclylalkylamino such as cycloalkylalkylamino and arylalkylamino;heterocyclylalkylamino substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkylamino;carbocyclylsulfamoyl such as cycloalkylsulfamoyl and arylsulfamoyl,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylsulfamoyl;heterocyclylsulfamoyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylsulfamoyl;carbocyclylsulfonyl such as cycloalkylsulfonyl and arylsulfonyl,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylsulfonyl such as cycloalkylsulfonyl and arylsulfonyl;heterocyclylsulfonyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylsulfonyl;carbocyclylcarbamoyl such as cycloalkylcarbamoyl and arylcarbamoyl,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylcarbamoyl such as cycloalkylcarbamoyl and arylcarbamoyl;heterocyclylcarbamoyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylcarbamoyl;carbocyclylalkylcarbamoyl such as cycloalkylalkylcarbamoyl andarylalkylcarbamoyl, substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted carbocyclylalkylcarbamoyl such as cycloalkylalkylcarbamoyland arylalkylcarbamoyl;heterocyclylalkylcarbamoyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkylcarbamoyl;carbocyclyloxycarbonyl such as cycloalkyloxycarbonyl andaryloxycarbonyl, substituted with one or more substituents selected fromthe substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted carbocyclyloxycarbonyl such as cycloalkyloxycarbonyl andaryloxycarbonyl;heterocyclyloxycarbonyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclyloxycarbonyl;alkylenedioxy substituted with halogen, or unsubstituted alkylenedioxy;oxo; andazide.

The aforementioned ring of ring A and ring B each may be substitutedwith one or more substituents selected from them.

In the specification, examples of the substituent of “substituted orunsubstituted carbocycle”, “substituted or unsubstituted benzene”,“substituted or unsubstituted heterocycle”, “substituted orunsubstituted pyridine”, “substituted or unsubstituted pyrimidine” and“substituted or unsubstituted pyrazine” in ring A′ and ring B includehalogen, cyano, hydroxy, nitro, carboxy, alkyl substituted with one ormore substituents selected from the substituent group α, unsubstitutedalkyl, alkoxy substituted with one or more substituents selected fromthe substituent group α, unsubstituted alkoxy, amino substituted withone or more substituents selected from the substituent group α,unsubstituted amino, carbamoyl substituted with one or more substituentsselected from the substituent group α, unsubstituted carbamoyl,alkoxycarbonyl substituted with one or more substituents selected fromthe substituent group α, and unsubstituted alkoxycarbonyl.

Examples of the substituents other than “—Z-ring B” of “substituted orunsubstituted carbocycle” or “substituted or unsubstituted heterocycle”in ring A include halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,alkynyloxy, or cyano.

Examples of the substituents of “substituted or unsubstitutedcarbocycle”, “substituted or unsubstituted benzene” or “substituted orunsubstituted heterocycle” in ring A′ include halogen.

Examples of the substituents of “substituted or unsubstitutedcarbocycle”, “substituted or unsubstituted heterocycle”, “substituted orunsubstituted pyridine”, “substituted or unsubstituted pyrimidine”, or“substituted or unsubstituted pyrazine” in ring B include halogen,alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, or cyano.

Examples of the substituents of “substituted or unsubstitutedcarbocyclic group”, “substituted or unsubstituted carbocyclylthio”,“substituted or unsubstituted carbocyclyloxycarbonyl”, “substituted orunsubstituted heterocyclyl”, “substituted or unsubstitutedcarbocyclyloxy”, “substituted or unsubstituted carbocyclylsulfinyl”,“substituted or unsubstituted carbocyclylsulfonyl”, “substituted orunsubstituted carbocycle”, “substituted or unsubstituted heterocyclyl”,“substituted or unsubstituted heterocyclyloxy”, “substituted orunsubstituted heterocyclylthio”, “substituted or unsubstitutedheterocyclyloxycarbonyl”, “substituted or unsubstitutedheterocycylsulfinyl”, “substituted or unsubstitutedheterocyclylsulfonyl”, “substituted or unsubstituted heterocycle”,“substituted or unsubstituted cyclopentane”, “substituted orunsubstituted cyclopentene”, “substituted or unsubstituted cyclohexane”and “substituted or unsubstituted cyclohexene” in other than the abovering A, ring A′ and ring B include one or more substituents selectedfrom the substituent group α, unsubstituted alkyl, and alkyl substitutedwith one or more substituents selected from the substituent group α.

The term “alkylene” include a linear or branched divalent carbon chainof a carbon number of 1 to 10, for example, a carbon number of 1 to 6,or a carbon number of 1 to 3. Examples include methylene, dimethylene,trimethylene, tetramethylene, and methyltrimethylene.

The alkylene portion in “alkylenedioxy” s the same as the above“alkylene.”

The term “alkenylene” includes a linear or branched divalent carbonchain of a carbon number of 2 to 10, for example, a carbon number of 2to 6, or a carbon number of 2 to 4, having a double bond at anyavailable position. Examples include vinylene, propenylene, butenylene,butadienylene, methylpropenylene, pentenylene and hexenylene.

The term “alkynylene”, includes a linear or branched divalent carbonchain of a carbon number of 2 to 10, for example, a carbon number of 2to 6, or a carbon number of 2 to 4, having a triple bond at anyavailable position and, further, optionally having a double bond.Examples include ethynylene, propynylene, butynylene, pentynylene andhexynylene.

Examples of the substituents of “substituted or unsubstituted alkylene”,“substituted or unsubstituted alkenylene”, and “substituted orunsubstituted alkynylene” include a group(s) selected from thesubstituent group α, and specific examples are halogen and hydroxy.

In formula (I), examples of groups wherein

wherein each symbol is the same as defined in the item (1),include,

These groups may be substituted with one or more selected from alkylsubstituted with one or more selected from the substituent group α,unsubstituted alkyl and alkyl substituted with one or more substituentsselected from the substituent group α at any available position.

Examples of groups wherein

wherein each symbol is the same as defined in the item (1), and Q′ issubstituted or unsubstituted carbocycle,include

These groups may be substituted with one or more selected from alkylsubstituted with one or more selected from the substituent group α,unsubstituted alkyl and alkyl substituted with one or more substituentsselected from the substituent group α at any available position.

The phrase “R^(za) and R^(zb) together with the carbon atom to whichthey are attached may form a substituted or unsubstituted non-aromaticcarbocycle or a substituted or unsubstituted non-aromatic heterocycle”include the following examples.

These groups may be substituted with one or more selected from alkylsubstituted with one or more selected from the substituent group α,unsubstituted alkyl and alkyl substituted with one or more substituentsselected from the substituent group α at any available position.

The phrases “R^(3a) and R^(3b) together with the carbon atom to whichthey are attached may form a substituted or unsubstituted carbocycle ora substituted or unsubstituted heterocycle” and “R^(4a) and R^(4b)together with the carbon atom to which they are attached may form asubstituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle” include the following examples.

These groups may be substituted with one or more selected from alkylsubstituted with one or more selected from the substituent group α,unsubstituted alkyl and alkyl substituted with one or more substituentsselected from the substituent group α at any available position.

In the specification, the term “solvate” includes, for example, solvateswith organic solvents and hydrates. It can be prepared in accordancewith the known methods. Examples of solvate include a solvate withacetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuranor diethyl ether. For example, it includes a non-toxic and water-solublehydrate or solvate such as a solvate with ethanol. In the case that ahydrate or solvate is formed, the compound or salt may be coordinatedwith any number of solvate molecules or water molecules.

The compound of the formula (I) includes a pharmaceutically acceptablesalt. Examples include salts with alkali metals such as lithium, sodiumor potassium; alkaline earth metals such as calcium; magnesium;transition metals such as zinc or iron; ammonium; organic bases; andamino acids; or salts with inorganic acids such as hydrochloric acid,sulfuric, nitric acid, hydrobromic acid, phosphoric acid or hydroiodicacid; and organic acids such as acetic acid, trifluoroacetic acid,citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid,fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid,phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid,methanesulfonic acid or ethanesulfonic acid. Specific examples arehydrochloric acid, phosphoric acid, tartaric acid and methanesulfonicacid. These salts can be formed by ordinary methods.

In addition, the compound of the formula (I) is not limited to aspecific isomer, but includes all possible isomers, such as keto-enolisomers, imine-enamine isomers, diastereoisomers, optical isomers androtation isomers; and racemate. For example, the compound of the formula(I) wherein R^(2a) is hydrogen includes the following tautomers.

The compounds of the formulas (Ia) to (If) mentioned below also includesimilar tautomers.

The compound of the formula (I) has an asymmetric carbon atom and thecompound includes the following optical isomers.

Preferable example is as follows:

The optical isomer of the compound of the formula (I) can be obtainedwith known methods such as chiral chromatography or diastereomer saltformation using an optical active acid or base.

In addition, one or more hydrogen, carbon or other atoms of the compoundof the formula (I) can be replaced by an isotope of the hydrogen, carbonor other atoms. Compounds of the formula (I) include all radiolabeledforms of compounds of the formula (I). The “radiolabeled,” “radiolabeledform” and the like of the compound of the formula (I) are encompassed bythe present invention and useful as a research and/or diagnostic tool inmetabolism pharmacokinetic studies and in binding assays. It is alsouseful for a medicament.

Examples of isotopes that can be incorporated into the compound of theformula (I) of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³Iand ³⁶Cl, respectively. Radiolabeled compounds of the invention can beprepared by methods known in the art. For example, tritiated compoundsof formula (I) can be prepared by introducing tritium into theparticular compound of formula (I), for example, by catalyticdehalogenation with tritium. This method may include reacting a suitablyhalogen-substituted precursor of a compound of formula (I) with tritiumgas in the presence of a suitable catalyst such as Pd/C, in the presenceor absence of a base. Other suitable methods for preparing tritiatedcompounds can be found in Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A) Chapter 6, (1987).¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon.

(General Procedures)

The compounds of the formulas (I) and (Ia) to (If) of the presentinvention can be prepared by the methods described below. In thefollowing steps, when a substituent which interferes with the reaction,e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy, is possessed,the substituent is protected by the method such as those described inProtective Groups in organic Synthesis, and Theodora W Greene (JohnWiley & Sons) in advance, and the protective group may be removed at adesirable step.

1) Synthesis of Compound (Ia)

wherein each symbol is the same as defined above.Step 1

Compound b can be prepared by adding a titanium reagent such aschlorotitanium triisopropoxide to enolate, which is obtained by reactingan objective ester such as ethyl propionate in the presence of a basesuch as lithium diisopropylamide in a solvent such as toluene,dichloromethane and tetrahydrofuran, or a mixed solvent thereof, addingCompound a which can be prepared by the known methods, and reacting themat −80° C. to 30° C., preferably −80° C. to 0° C., for 0.1 to 24 hours,preferably 0.1 to 12 hours.

Step 2

Compound c can be prepared by adding a Grignard reagent such asmethylmagnesium bromide which is commercially available or can beprepared by the known methods or a reductant such as borane, sodiumborohydride and lithium aluminium hydride to Compound b in a solventsuch as dioxane, tetrahydrofuran, ether and toluene, or a mixed solventthereof, and reacting at −80° C. to 80° C., preferably −20° C. to 30°C., for 0.5 to 48 hours, preferably 1 to 12 hours.

Step 3

Compound d can be prepared by reacting Compound c in the presence of anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid andtrifluoroacetic acid in a solvent such as dioxane, methanol anddichloromethane, or a mixed solvent thereof at 0° C. to 80° C.,preferably 0° C. to 30° C. for 0.5 to 48 hours, preferably 1 to 24hours.

Step 4

Compound e can be prepared by adding isothiocyanate having a protectivegroup such as benzoyl isothiocyanate which is commercially available oris prepared by the known methods to Compound d in a solvent such asdioxane, tetrahydrofuran, toluene, and acetone, or a mixed solventthereof and reacting at −30 to 50° C., preferably −10 to 25° C. for 0.1to 12 hours, preferably 0.1 to 3 hours.

Step 5

Compound (Ia) can be prepared by adding an alkylating agent such asmethyl iodide, diethyl sulfate and benzyl bromide to Compound e in thepresence or absence of a base such as diisopropyl ethyl amine,triethylamine, pyridine and sodium hydroxide in a solvent such asmethanol, ethanol, dimethylformamide and tetrahydrofuran and reacting at0 to 200° C., preferably 40 to 150° C. for 1 to 48 hours, preferably 0.5to 24 hours.

2) Synthesis of Compound (Ib)

wherein each symbol is the same as defined above.Step 1

Compound f can be prepared by adding Compound a which can be prepared bythe known methods to a Grignard reagent such as allylmagnesium bromidein a solvent such as toluene, dichloromethane and tetrahydrofuran, or amixed solvent thereof and reacting at −80 to 30° C., preferably −80 to0° C. for 0.1 to 24 hours, preferably 0.1 to 12 hours.

Step 2

Compound g can be prepared by reacting Compound f which is prepared inStep 1 in the presence of an acid such as hydrochloric acid, hydrobromicacid, sulfuric acid and trifluoroacetic acid in a solvent such asdioxane, methanol and dichloromethane, or a mixed solvent thereof at 0to 80° C., preferably 0 to 30° C. for 0.5 to 48 hours, preferably 1 to24 hours.

Step 3

Compound h can be prepared by adding isocyanate having a protectivegroup such as benzoyl isocyanate which is commercially available or isprepared by the known methods to Compound g in a solvent such asdichloromethane, dioxane, tetrahydrofuran, toluene, and acetone, or amixed solvent thereof and reacting at −30 to 50° C., preferably −10 to25° C. for 0.1 to 12 hours, preferably 0.1 to 3 hours.

Step 4

Compound (Ib) can be prepared by adding a halogenium cation source suchas iodine, bromine, N-bromosuccinimide (NBS) to Compound h in a solventsuch as dichloromethane and reacting at −20 to 40° C., preferably 0 to20° C. for 0.1 to 12 hours, preferably 0.1 to 6 hours, followed byadding a base such as pyrrolidine, piperidine, piperazine and morpholineand reacting at 20 to 100° C., preferably 40 to 80° C. for 0.1 to 24hours, preferably 1 to 12 hours.

3) Synthesis of Compound (Ic)

wherein each symbol is the same as defined above.Step 1

Compound i can be prepared by adding a titanium reagent such aschlorotitanium triisopropoxide to enolate which can be prepared from anobjective carbonyl compound such as diethyl ketone in the presence of abase such as lithium diisopropylamide in a solvent such as toluene,dichloromethane, tetrahydrofuran, or a mixed solvent thereof, addingCompound a which can be prepared by the known methods and reacting themat −80° C. to 30° C., preferably −80° C. to 0° C., for 0.1 to 24 hours,preferably 0.1 to 12 hours.

Step 2

Compound j can be prepared by reacting Compound i in the presence of anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid andtrifluoroacetic acid in a solvent such as dioxane, methanol, anddichloromethane, or a mixed solvent thereof at 0 to 80° C., preferably 0to 30° C., for 0.5 to 48 hours, preferably 1 to 24 hours.

Step 3

Compound k can be prepared by adding isocyanate having a protectivegroup such as benzoyl isocyanate which is commercially available orprepared by the known methods to Compound j in a solvent such asdioxane, tetrahydrofuran, toluene and acetone, or a mixed solventthereof and reacting at −30 to 50° C., preferably −10 to 15° C. for 0.1to 12 hours, preferably 0.1 to 3 hours.

Step 4

Compound (Ic) can be prepared by adding concentrated sulfuric acid,concentrated nitric acid or the like and reacting them at 0 to 100° C.,preferably 0 to 60° C. for 0.5 to 24 hours, preferably 1 to 12 hours.

Compounds (Id) to (If), i.e., compounds of the formula (I) wherein

can be prepared, for example, by the procedures mentioned below.4) Synthesis of Compound (Id)

wherein Y^(a) is Y¹ or Y³, Y^(b) is Y² or Y⁴, a dashed line indicatesthe presence or absence of a bond, and other each symbol is the same asdefined above.Step 1

Compound l can be prepared by adding Compound a which can be prepared bythe known methods to enolate which is prepared by reacting an objectivecarbonyl compound such as cyclopentanone in the presence of a base suchas lithium diisopropyl amide in a solvent such as toluene,dichloromethane and tetrahydrofuran, or a mixed solvent thereof andreacting −80 to 30° C., preferably −80 to 0° C. for 0.1 to 24 hours,preferably 0.1 to 12 hours.

Step 2

Compound m can be prepared by reacting Compound l in the presence of anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid ortrifluoroacetic acid in a solvent such as dioxane, methanol anddichloromethane, or a mixed solvent thereof at 0 to 80° C., preferably 0to 30° C. for 0.5 to 48 hours, preferably 1 to 24 hours.

Step 3

Compound (Id) can be prepared by adding isocyanate having a protectivegroup such as benzoyl isocyanate which is commercially available orprepared by the known methods to Compound m, reacting at −30 to 50° C.,preferably −10 to 25° C. for 0.1 to 12 hours, preferably 0.1 to 3 hoursin a solvent such as dioxane, tetrahydrofuran, toluene and acetone, or amixed solvent thereof, and subsequently, adding concentrated sulfuricacid or concentrated nitric acid, followed by a reaction at 0 to 100°C., preferably 0 to 60° C., for 0.5 to 24 hours, preferably 1 to 12hours.

Compound (Id) wherein a dashed line means the absence of a bond can beprepared by preparing Compound (Id) wherein any one of a dashed linemeans the presence of a bond, followed by hydrogen addition under theusual conditions.

5) Synthesis of Compound (Ie)

wherein each symbol is the same as defined above.Step 1

Compound n can be prepared by adding Compound a which can be prepared bythe known methods to enolate which is prepared by reacting an objectivecarbonyl compound such as cyclopentanone in the presence of a base suchas lithium diisopropyl amide in a solvent such as toluene,dichloromethane and tetrahydrofuran, or a mixed solvent thereof andreacting at −80 to 30° C., preferably −80 to 0° C. for 0.1 to 24 hours,preferably 0.1 to 12 hours

Step 2

Compound o can be prepared by adding a Grignard reagent such asmethylmagnesium bromide which is commercially available or can beprepared by the known methods to Compound n in a solvent such asdioxane, tetrahydrofuran, ether and toluene, or a mixed solvent thereof,and reacting at −80 to 80° C., preferably −20 to 30° C. for 0.5 to 48hours, preferably 1 to 12 hours, followed by reacting in the presence ofan acid such as hydrochloric acid, hydrobromic acid, sulfuric acid ortrifluoroacetic acid at 0 to 80° C., preferably 0 to 30° C. for 0.5 to48 hours, preferably 1 to 24 hours.

Step 3

Compound p can be prepared by adding isocyanate having a protectivegroup such as benzoyl isocyanate which is commercially available orprepared by the known methods to Compound o, reacting at −30 to 50° C.,preferably −10 to 25° C., for 0.1 to 12 hours, preferably 0.1 to 3 hoursin a solvent such as dioxane, tetrahydrofuran, toluene and acetone, or amixed solvent thereof, and subsequently, adding concentrated sulfuricacid or concentrated nitric acid, followed by reacting at 0° C. to 100°C., preferably 0° C. to 60° C., for 0.5 to 24 hours, preferably 1 to 12hours.

Step 4

Compound (Ie) can be prepared by adding oxalyl chloride, thionylchloride or the like and a catalytic amount of N,N-dimethylformamide, orby adding a chlorinating reagent such as1-chloro-2-trimethylpropenylamine to a Compound p in a solvent such asdichloromethane, tetrahydrofuran and toluene and reacting at 0 to 100°C., preferably 10 to 50° C. for 0.5 to 72 hours, preferably 0.5 to 6hours.

6) Synthesis of Compound (If)

wherein each symbol is the same as defined above.Step 1

Compound q can be prepared by adding Compound a which can be prepared bythe known methods to a Grignard reagent such as phenylmagnesium bromidehaving an optionally protected hydroxy group at ortho position or alithium reagent such as pyridyl lithium having an optionally protectedhydroxy group at ortho position and reacting them in a solvent such astoluene, diethyl ether and tetrahydrofuran, or a mixed solvent thereofat −80 to 30° C., preferably −80 to 0° C. for 0.1 to 24 hours,preferably 0.1 to 12 hours, followed by removing a protective group ofthe hydroxy group by the known methods.

Step 2

Compound r can be prepared by reacting Compound q in the presence of anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid ortrifluoroacetic acid in a solvent such as dioxane, methanol anddichloromethane, or a mixed solvent thereof at 0° C. to 80° C.,preferably 0° C. to 30° C. for 0.5 to 48 hours, preferably 1 to 24hours.

Step 3

Compound s can be prepared by adding isothiocyanate having a protectivegroup which is commercially available or prepared by the known methodssuch as benzoyl isothiocyanate and reacting them in a solvent such asdioxane, tetrahydrofuran, toluene and acetone, or a mixed solventthereof at −30° C. to 50° C., preferably −10° C. to 25° C. for 0.1 to 12hours, preferably 0.1 to 3 hours.

Step 4

Compound (If) can be prepared by reacting Compound s with an alkylatingagent such as methyl iodide, diethyl sulfate and benzyl bromide in thepresence or absence of a base such as diisopropyl ethyl amine,triethylamine, pyridine, sodium hydroxide in a solvent such as methanol,ethanol, dimethylformamide and tetrahydrofuran at 0° C. to 200° C.,preferably 40° C. to 150° C. for 1 to 48 hours, preferably 0.5 to 24hours.

In the above all steps, an order of steps to be implemented may beappropriately changed, and each intermediate may be isolated, and usedin a next step.

7) Conversion of a Substituent

Above-mentioned Compounds (Ia) to (If) and compounds wherein ring A issubstituted with various substituent, for example, ring B—Z— group orthe like, can be prepared according to the method mentioned above or theknown methods such as methods described in Patent Document 2, PatentDocument 3, Patent Document 4 and the like.

Moreover, the optically active isomer of the compound (I) can beprepared by using an optically active compound as a starting material,performing an asymmetric synthesis in the suitable step to prepare anoptically active intermediate, or optical resolution of the racemate ofthe intermediate or the objective compound in the appropriate step. Themethod of optical resolution include the separation of optical isomerusing an optically active column, the kinetics optical resolution usingenzyme reactions or the like, the crystallization and separation ofdiastereomers by the salt formation using chiral acids or chiral bases,the preferential crystallization or the like.

Specific embodiments of the present invention are illustrated below.Each symbol is as defined above.

(A)

In the formula (I), the followings are exemplified.

Ring A includes substituted carbocycle or substituted or unsubstitutedheterocycle.

Ring A includes

Ring A′ and ring B are each independently substituted or unsubstitutedcarbocycle or substituted or unsubstituted heterocycle,L¹, L², and L³ are each independently a bond, substituted orunsubstituted alkynylene, substituted or unsubstituted alkenylene orsubstituted or unsubstituted alkynylene, ═W¹ is ═O, ═S, or ═NR⁹,W² is O, S, or N(R⁸),R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,R⁹ is hydrogen, hydroxy, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,when ring A is (i), then the constituent carbon atom of L¹- and theconstituent carbon atom of L², or the constituent carbon atom of L¹ andthe nitrogen atom of W² may be connected with substituted orunsubstituted alkylene to form a ring,when ring A is (ii), then the constituent carbon atom of L¹ and theconstituent carbon atom of L², or the nitrogen atom of W² and theconstituent carbon atom of L² may be connected with substituted orunsubstituted alkylene to form a ringwhen ring A is (iii), then two nitrogen atoms of W² may be connectedwith substituted or unsubstituted alkylene to form a ring,when ring A is (vi), then the constituent carbon atom of L¹ and theconstituent carbon atom of L² may be connected with substituted orunsubstituted alkylene to form a ring,p is 1 or 2, andwhen multiple L³, multiple W², or multiple R⁹ are present, each of themmay be independently different.

Ring A includes

wherein L is each independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted alkenylene, substituted orunsubstituted alkynylene, ring T is a ring which may be substituted witha group(s) selected from the substituent group α, and other each symbolis the same as defined above.

Ring A includes

Ring A includes

L¹ and L² include each independently a bond, substituted orunsubstituted alkylene, substituted or unsubstituted alkenylene orsubstituted or unsubstituted alkynylene, and

R⁸ includes hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl.

R⁸ includes hydrogen.

Ring A includes

Ring A′ and ring B include each independently substituted orunsubstituted carbocycle or substituted or unsubstituted heterocycle.

Ring A′ is, for example, substituted or unsubstituted benzene and ring Bis substituted or unsubstituted pyridine, substituted or unsubstitutedpyrimidine or substituted or unsubstituted pyrazine.

R¹ includes substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group.

R¹ includes substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group.

R¹ is, for example, C1 to C3 unsubstituted alkyl.

R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl.

R^(2a) and R^(2b) are, for example, both hydrogen.

As one aspect in substituent (r-a), R^(za) and R^(zb) each independentlyinclude hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted amino, substituted or unsubstituted carbamoyl, substitutedor unsubstituted thiocarbamoyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, or substituted orunsubstituted heterocyclyloxycarbonyl, or R^(za) and R^(zb) togetherwith the carbon atom to which they are attached may form a substitutedor unsubstituted carbocycle or a substituted or unsubstitutedheterocycle.

As one aspect in substituent (r-a), examples of R^(za) and R^(zb) areeach independently hydrogen, halogen and substituted or unsubstitutedalkyl, or R^(za) and R^(zb) together with the carbon atom to which theyare attached may form a substituted or unsubstituted carbocycle.

As one aspect in substituent (r-a), examples of R^(za) and R^(zb) areeach independently, hydrogen, halogen and substituted or unsubstitutedalkyl.

As one aspect in substituent (r-b), the dashed a means, for example, thepresence of a bond.

As one aspect in substituent (r-b), the dashed line a means, forexample, the absence of a bond.

As one aspect in substituent (r-b), R^(3a) and R^(3b) are eachindependently, hydrogen, halogen, hydroxy, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl, or R^(3a) and R^(3b) together withthe carbon atom to which they are attached may form a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,and when dashed line a means the presence of a bond, then R^(3b) isabsent.

As one aspect in substituent (r-b), examples of R^(3a) and R^(3b) areeach independently, hydrogen, halogen, hydroxy, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstituted amino,substituted or unsubstituted carbamoyl, substituted or unsubstitutedthiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl, and when the dashed line a means thepresence of a bond, then R^(3b) is absent.

As one aspect in substituent (r-b), R^(3a) is, for example, alkyl,R^(3b) is, for example, hydrogen, and the dashed line a means theabsence of a bond.

As one aspect in substituent (r-b), both of R^(3a) and R^(3b) arehydrogen, and the dashed line a means the absence of a bond.

As one aspect in substituent (r-b), R^(3a) is, for example, hydrogen andthe dashed line a means the presence of a bond.

As one aspect in substituent (r-b), R^(3a) is, for example, alkyl, andthe dashed line a means the presence of a bond.

As one aspect in substituent (r-c), examples of R^(3c) are hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted amino, substituted or unsubstituted carbamoyl,substituted or unsubstituted thiocarbamoyl, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, a substituted or unsubstituted carbocyclic group,substituted or unsubstituted carbocyclyloxycarbonyl, a substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclyloxycarbonyl, and when the dashed line b means the presenceof a bond, then R^(3c) is absent.

As one aspect in substituent (r-c), R^(3c) is, for example, hydrogen andthe dashed line b means the absence of a bond.

As one aspect in substituent (r-c), R^(3c) is, for example, absent andthe dashed line b means the presence of a bond.

As one aspect in substituent (r-a), (r-b) and/or (r-c), R^(4a), R^(4b)and R^(4c) are each independently, hydrogen, halogen, hydroxy,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl, R^(4a) and R^(4b) together with thecarbon atom to which they are attached may form a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,and when the dashed line a means the presence of a bond, then R^(4b) isabsent and when the dashed line c means the presence of a bond, thenR^(4c) is absent.

As one aspect in substituent (r-a), (r-b), or (r-c), R^(4a), R^(4b), andR^(4c) are each independently, for example, hydrogen, halogen, hydroxy,substituted or unsubstituted alkyl, substituted or unsubstituted alkenylor substituted or unsubstituted alkynyl and when the dashed line a meansthe presence of a bond, then R^(4b) is absent, and when the dashed linec means the presence of a bond, then R^(4c) is absent.

As one aspect in substituent (r-a), for example, both of R^(4a) andR^(4b) are hydrogen.

As one aspect in substituent (r-b), for example, both of R^(4a) andR^(4b) are hydrogen and the dashed line a means the absence of a bond.

As one aspect in substituent (r-b), R^(4a) is, for example, hydrogen andthe dashed line a means the presence of a bond.

As one aspect in substituent (r-c), R^(4c) is, for example, hydrogen andthe dashed line c means the absence of a bond.

As one aspect in substituent (r-c), R^(4c) is, for example, absent andthe dashed line c means the presence of a bond.

As one aspect in substituent (r-c) or (r-d), ring Q is, for example,substituted or unsubstituted carbocycle or substituted or unsubstitutedheterocycle.

As one aspect in substituent (r-c), Y¹ and Y² are each independently—C(R⁵)(R⁶)—, —C(R⁵)═, —N(R⁷)—, —N═, —S—, —SO—, —SO₂—, or —O—.

As one aspect in substituent (r-c), Y¹ and Y² are, for example, eachindependently —C(R⁵)(R⁶)— or —C(R⁵)═.

As one aspect in substituent (r-d), Y³ and Y⁴ are each independently—C(R⁵)(R⁶)—, —N(R⁷)—, —S—, —SO—, —SO₂—, or —O—.

As one aspect in substituent (r-d), Y³ and Y⁴ are, for example, eachindependently —C(R⁵)(R⁶)—.

As one aspect in substituent (r-c) or (r-d), R⁵ and R⁶ are, for example,each independently, hydrogen, halogen, hydroxy, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylthio, substituted orunsubstituted alkenylthio, substituted or unsubstituted alkynylthio,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino,substituted or unsubstituted carbamoyl, substituted or unsubstitutedthiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

As one aspect in substituent (r-c) or (r-d), R⁵ and R⁶ are, for example,each independently hydrogen, halogen, hydroxy, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstituted amino,substituted or unsubstituted carbamoyl, substituted or unsubstitutedthiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted orunsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl.

As one aspect in substituent (r-c) or (r-d), R⁵ and R⁶ are, for example,each independently, hydrogen, halogen, hydroxy, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, cyano, nitro, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted amino or substituted orunsubstituted carbamoyl.

As one aspect in substituent (r-c) or (r-d), R⁷ is hydrogen, halogen,hydroxy, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedacyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted amino, substitutedor unsubstituted carbocyclic group, substituted or unsubstitutedcarbocyclyloxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclyloxycarbonyl, substituted orunsubstituted heterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

As one aspect in substituent (r-c) or (r-d), R⁷ is, for example,hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted acyl, cyano,nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted thiocarbamoyl, substituted or unsubstituted amino,substituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

As one aspect in substituent (r-c) or (r-d), R⁷ is, for example,hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted acyl, cyano, carboxy, substituted orunsubstituted alkoxycarbonyl, or substituted or unsubstituted carbamoyl.

is, for example,

is, for example,

is, for example,

is, for example,

is, for example,

is, for example,

is, for example,

is, for example,

is, for example,

and more specifically,

Any available position in these groups may be substituted with one ormore substituents selected from substituent group α, unsubstituted alkyland alkyl substituted with one or more substituents selected from thesubstituent group α.

is, for example,

Any available position in these groups may be substituted with one ormore substituents selected from substituent group α, unsubstituted alkyland alkyl substituted with one or more substituents selected from thesubstituent group α.

is, for example,

and more specifically,

Any available position in these groups may be substituted with one ormore substituents selected from substituent group α, unsubstituted alkyland alkyl substituted with one or more substituents selected from thesubstituent group α.

As one aspect in the compound (I), the following compound isexemplified:

wherein ring A′ is substituted or unsubstituted carbocycle wherein thesubstituent is, for example, halogen,ring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazinewherein the substituent is, for example, halogen, hydroxy, alkoxy, aminoor cyano,R¹ is substituted or unsubstituted alkyl, more specifically, R¹ isunsubstituted alkyl,R⁸ is hydrogen, substituted or unsubstituted alkyl or substituted orunsubstituted acyl, more specifically, R⁸ is hydrogen,R^(za) and R^(zb) are each independently hydrogen or substituted orunsubstituted alkyl, more specifically, both of R^(za) and R^(zb) arehydrogen.

As another aspect, the following compound is exemplified:

wherein ring A′ is substituted or unsubstituted carbocycle wherein thesubstituent is, for example, halogen; or substituted or unsubstitutedthiophen wherein the substituent is, for example, halogen,ring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazinewherein the substituent is, for example, halogen, hydroxy, alkyl,halogeno alkyl, alkynyl, alkoxy, halogenoalkoxy, amino or cyano,R¹ is substituted or unsubstituted alkyl, more specifically, R¹ isunsubstituted alkyl,R⁸ is hydrogen, substituted or unsubstituted alkyl or substituted orunsubstituted acyl, more specifically, R⁸ is hydrogen.

As other embodiment, the following compound is exemplified:

wherein ring A′ is substituted or unsubstituted carbocycle wherein thesubstituent is, for example, halogen,ring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazinewherein the substituent is, for example, halogen, hydroxy, alkyl,halogeno alkyl, alkoxy, halogenoalkoxy, amino or cyano,R¹ is substituted or unsubstituted alkyl, more specifically, R¹ isunsubstituted alkyl,R³ is hydrogen or substituted or unsubstituted alkyl, more specifically,R³ is unsubstituted alkyl,R⁸ is hydrogen, substituted or unsubstituted alkyl or substituted orunsubstituted acyl, more specifically, R⁸ is hydrogen.

As another aspect, the compound of the formula (I) wherein

wherein Me is methyl;the compound of the formula (I) wherein ring A is

the compound of the formula (I) wherein ring B is

wherein R^(b1) and R^(b2) are each independently hydrogen, chloro,fluoro, methoxy, butynyloxy, cyano, amino, or carbamoyl;the compound of the formula (I) wherein the combination of ring B,R^(b1), and R^(b2) (B, R^(b1), R^(b2)) is as follows:(B1, hydrogen, hydrogen) (hereinafter referred to as ring B is b1)(B1, hydrogen, chloro) (hereinafter referred to as ring B is b2)(B1, hydrogen, fluoro) (hereinafter referred to as ring B is b3),(B1, hydrogen, methoxy) (hereinafter referred to as ring B is b4),(B1, hydrogen, butynyloxy) (hereinafter referred to as ring B is b5),(B1, hydrogen, cyano) (hereinafter referred to as ring B is b6),(B1, hydrogen, amino) (hereinafter referred to as ring B is b7),(B1, hydrogen, carbamoyl) (hereinafter referred to as ring B is b8),(B1, chloro, hydrogen) (hereinafter referred to as ring B is b9),(B1, chloro, chloro) (hereinafter referred to as ring B is b10),(B1, chloro, fluoro) (hereinafter referred to as ring B is b11),(B1, chloro, methoxy) (hereinafter referred to as ring B is b12),(B1, chloro, butynyloxy) (hereinafter referred to as ring B is b13),(B1, chloro, cyano) (hereinafter referred to as ring B is b14),(B1, chloro, amino) (hereinafter referred to as ring B is b15),(B1, chloro, carbamoyl) (hereinafter referred to as ring B is b16),(B1, fluoro, hydrogen) (hereinafter referred to as ring B is b17),(B1, fluoro, chloro) (hereinafter referred to as ring B is b18),(B1, fluoro, fluoro) (hereinafter referred to as ring B is b19),(B1, fluoro, methoxy) (hereinafter referred to as ring B is b20),(B1, fluoro, butynyloxy) (hereinafter referred to as ring B is b21),(B1, fluoro, cyano) (hereinafter referred to as ring B is b22),(B1, fluoro, amino) (hereinafter referred to as ring B is b23),(B1, fluoro, carbamoyl) (hereinafter referred to as ring B is b24),(B1, methoxy, hydrogen) (hereinafter referred to as ring B is b25),(B1, methoxy, chloro) (hereinafter referred to as ring B is b26),(B1, methoxy, fluoro) (hereinafter referred to as ring B is b27),(B1, methoxy, methoxy) (hereinafter referred to as ring B is b28),(B1, methoxy, butynyloxy) (hereinafter referred to as ring B is b29),(B1, methoxy, cyano) (hereinafter referred to as ring B is b30),(B1, methoxy, amino) (hereinafter referred to as ring B is b31),(B1, methoxy, carbamoyl) (hereinafter referred to as ring B is b32),(B1, butynyloxy, hydrogen) (hereinafter referred to as ring B is b33),(B1, butynyloxy, chloro) (hereinafter referred to as ring B is b34),(B1, butynyloxy, fluoro) (hereinafter referred to as ring B is b35),(B1, butynyloxy, methoxy) (hereinafter referred to as ring B is b36),(B1, butynyloxy, cyano) (hereinafter referred to as ring B is b37),(B1, butynyloxy, amino) (hereinafter referred to as ring B is b38),(B1, butynyloxy, carbamoyl) (hereinafter referred to as ring B is b39),(B1, cyano, hydrogen) (hereinafter referred to as ring B is b40),(B1, cyano, chloro) (hereinafter referred to as ring B is b41),(B1, cyano, fluoro) (hereinafter referred to as ring B is b42),(B1, cyano, methoxy) (hereinafter referred to as ring B is b43),(B1, cyano, butynyloxy) (hereinafter referred to as ring B is b44),(B1, cyano, cyano) (hereinafter referred to as ring B is b45),(B1, cyano, amino) (hereinafter referred to as ring B is b46),(B1, cyano, carbamoyl) (hereinafter referred to as ring B is b47),(B1, amino, hydrogen) (hereinafter referred to as ring B is b48),(B1, amino, chloro) (hereinafter referred to as ring B is b49),(B1, amino, fluoro) (hereinafter referred to as ring B is b50),(B1, amino, methoxy) (hereinafter referred to as ring B is b51),(B1, amino, butynyloxy) (hereinafter referred to as ring B is b52),(B1, amino, cyano) (hereinafter referred to as ring B is b53),(B1, carbamoyl, hydrogen) (hereinafter referred to as ring B is b54),(B1, carbamoyl, chloro) (hereinafter referred to as ring B is b55),(B1, carbamoyl, fluoro) (hereinafter referred to as ring B is b56),(B1, carbamoyl, methoxy) (hereinafter referred to as ring B is b57),(B1, carbamoyl, butynyloxy) (hereinafter referred to as ring B is b58),(B1, carbamoyl, cyano) (hereinafter referred to as ring B is b59),(B3, hydrogen, hydrogen) (hereinafter referred to as ring B is b60),(B3, hydrogen, chloro) (hereinafter referred to as ring B is b61),(B3, hydrogen, fluoro) (hereinafter referred to as ring B is b62),(B3, hydrogen, methoxy) (hereinafter referred to as ring B is b63),(B3, hydrogen, butynyloxy) (hereinafter referred to as ring B is b64),(B3, hydrogen, cyano) (hereinafter referred to as ring B is b65),(B3, hydrogen, amino) (hereinafter referred to as ring B is b66),(B3, hydrogen, carbamoyl) (hereinafter referred to as ring B is b67),(B3, chloro, hydrogen) (hereinafter referred to as ring B is b68),(B3, chloro, chloro) (hereinafter referred to as ring B is b69),(B3, chloro, fluoro) (hereinafter referred to as ring B is b70),(B3, chloro, methoxy) (hereinafter referred to as ring B is b71),(B3, chloro, butynyloxy) (hereinafter referred to as ring B is b72),(B3, chloro, cyano) (hereinafter referred to as ring B is b73),(B3, chloro, amino) (hereinafter referred to as ring B is b74),(B3, chloro, carbamoyl) (hereinafter referred to as ring B is b75),(B3, fluoro, hydrogen) (hereinafter referred to as ring B is b76),(B3, fluoro, chloro) (hereinafter referred to as ring B is b77),(B3, fluoro, fluoro) (hereinafter referred to as ring B is b78),(B3, fluoro, methoxy) (hereinafter referred to as ring B is b79),(B3, fluoro, butynyloxy) (hereinafter referred to as ring B is b80),(B3, fluoro, cyano) (hereinafter referred to as ring B is b81),(B3, fluoro, amino) (hereinafter referred to as ring B is b82),(B3, fluoro, carbamoyl) (hereinafter referred to as ring B is b83),(B3, methoxy, hydrogen) (hereinafter referred to as ring B is b84),(B3, methoxy, chloro) (hereinafter referred to as ring B is b85),(B3, methoxy, fluoro) (hereinafter referred to as ring B is b86),(B3, methoxy, methoxy) (hereinafter referred to as ring B is b87),(B3, methoxy, butynyloxy) (hereinafter referred to as ring B is b88),(B3, methoxy, cyano) (hereinafter referred to as ring B is b89),(B3, methoxy, amino) (hereinafter referred to as ring B is b90),(B3, methoxy, carbamoyl) (hereinafter referred to as ring B is b91),(B3, butynyloxy, hydrogen) (hereinafter referred to as ring B is b92),(B3, butynyloxy, chloro) (hereinafter referred to as ring B is b93),(B3, butynyloxy, fluoro) (hereinafter referred to as ring B is b94),(B3, butynyloxy, methoxy) (hereinafter referred to as ring B is b95),(B3, butynyloxy, cyano) (hereinafter referred to as ring B is b96),(B3, butynyloxy, amino) (hereinafter referred to as ring B is b97),(B3, butynyloxy, carbamoyl) (hereinafter referred to as ring B is b98),(B3, cyano, hydrogen) (hereinafter referred to as ring B is b99),(B3, cyano, chloro) (hereinafter referred to as ring B is b100),(B3, cyano, fluoro) (hereinafter referred to as ring B is b101),(B3, cyano, methoxy) (hereinafter referred to as ring B is b102),(B3, cyano, butynyloxy) (hereinafter referred to as ring B is b103),(B3, cyano, cyano) (hereinafter referred to as ring B is b104),(B3, cyano, amino) (hereinafter referred to as ring B is b105),(B3, cyano, carbamoyl) (hereinafter referred to as ring B is b106),(B3, amino, hydrogen) (hereinafter referred to as ring B is b107),(B3, amino, chloro) (hereinafter referred to as ring B is b108),(B3, amino, fluoro) (hereinafter referred to as ring B is b109),(B3, amino, methoxy) (hereinafter referred to as ring B is b110),(B3, amino, butynyloxy) (hereinafter referred to as ring B is bill),(B3, amino, cyano) (hereinafter referred to as ring B is b112),(B3, carbamoyl, hydrogen) (hereinafter referred to as ring B is b113),(B3, carbamoyl, chloro) (hereinafter referred to as ring B is b114),(B3, carbamoyl, fluoro) (hereinafter referred to as ring B is b115),(B3, carbamoyl, methoxy) (hereinafter referred to as ring B is b116),(B3, carbamoyl, butynyloxy) (hereinafter referred to as ring B is b117),or(B3, carbamoyl, cyano) (hereinafter referred to as ring B is b118),the compound of the formula (I) wherein the combination of rings B andR^(b1) (B, R^(b1)) is as follows:(B2, hydrogen) (hereinafter referred to as Ring B is b119),(B2, chloro) (hereinafter referred to as Ring B is b120),(B2, fluoro) (hereinafter referred to as Ring B is b121),(B2, methoxy) (hereinafter referred to as Ring B is b122),(B2, butynyloxy) (hereinafter referred to as Ring B is b123),(B2, cyano) (hereinafter referred to as Ring B is b124),(B2, amino) (hereinafter referred to as Ring B is b125),(B2, carbamoyl) (hereinafter referred to as Ring B is b126),(B4, hydrogen) (hereinafter referred to as Ring B is b127),(B4, chloro) (hereinafter referred to as Ring B is b128),(B4, fluoro) (hereinafter referred to as Ring B is b129),(B4, methoxy) (hereinafter referred to as Ring B is b130),(B4, butynyloxy) (hereinafter referred to as Ring B is b131),(B4, cyano) (hereinafter referred to as Ring B is b132),(B4, amino) (hereinafter referred to as Ring B is b133) or(B4, carbamoyl)(hereinafter referred to as Ring B is b134).In the formula (I), the combination of

ring A and ring B (r, A, b) is as follows:(r1,A1,b1),(r1,A1,b2),(r1,A1,b3),(r1,A1,b4),(r1,A1,b5),(r1,A1,b6),(r1,A1,b7),(r1,A1,b8),(r1,A1,b9),(r1,A1,b10),(r1,A1,b11),(r1,A1,b12),(r1,A1,b13),(r1,A1,b14),(r1,A1,b15),(r1,A1,b16),(r1,A1,b17),(r1,A1,b18),(r1,A1,b19),(r1,A1,b20),(r1,A1,b21),(r1,A1,b22),(r1,A1,b23),(r1,A1,b24),(r1,A1,b25),(r1,A1,b26),(r1,A1,b27),(r1,A1,b28),(r1,A1,b29),(r1,A1,b30),(r1,A1,b31),(r1,A1,b32),(r1,A1,b33),(r1,A1,b34),(r1,A1,b35),(r1,A1,b36),(r1,A1,b37),(r1,A1,b38),(r1,A1,b39),(r1,A1,b40),(r1,A1,b41),(r1,A1,b42),(r1,A1,b43),(r1,A1,b44),(r1,A1,b45),(r1,A1,b46),(r1,A1,b47),(r1,A1,b48),(r1,A1,b49),(r1,A1,b50),(r1,A1,b51),(r1,A1,b52),(r1,A1,b53),(r1,A1,b54),(r1,A1,b55),(r1,A1,b56),(r1,A1,b57),(r1,A1,b58),(r1,A1,b59),(r1,A1,b60),(r1,A1,b61),(r1,A1,b62),(r1,A1,b63),(r1,A1,b64),(r1,A1,b65),(r1,A1,b66),(r1,A1,b67),(r1,A1,b68),(r1,A1,b69),(r1,A1,b70),(r1,A1,b71),(r1,A1,b72),(r1,A1,b73),(r1,A1,b74),(r1,A1,b75),(r1,A1,b76),(r1,A1,b77),(r1,A1,b78),(r1,A1,b79),(r1,A1,b80),(r1,A1,b81),(r1,A1,b82),(r1,A1,b83),(r1,A1,b84),(r1,A1,b85),(r1,A1,b86),(r1,A1,b87),(r1,A1,b88),(r1,A1,b89),(r1,A1,b90),(r1,A1,b91),(r1,A1,b92),(r1,A1,b93),(r1,A1,b94),(r1,A1,b95),(r1,A1,b96),(r1,A1,b97),(r1,A1,b98),(r1,A1,b99),(r1,A1,b100),(r1,A1,b101),(r1,A1,b102),(r1,A1,b103),(r1,A1,b104),(r1,A1,b105),(r1,A1,b106),(r1,A1,b107),(r1,A1,b108),(r1,A1,b109),(r1,A1,b110),(r1,A1,b111),(r1,A1,b112),(r1,A1,b113),(r1,A1,b114),(r1,A1,b115),(r1,A1,b116),(r1,A1,b117),(r1,A1,b118),(r1,A1,b119),(r1,A1,b120),(r1,A1,b121),(r1,A1,b122),(r1,A1,b123),(r1,A1,b124),(r1,A1,b125),(r1,A1,b126),(r1,A1,b127),(r1,A1,b128),(r1,A1,b129),(r1,A1,b130),(r1,A1,b131),(r1,A1,b132),(r1,A1,b133),(r1,A1,b134),(r1,A2,b1),(r1,A2,b2),(r1,A2,b3),(r1,A2,b4),(r1,A2,b5),(r1,A2,b6),(r1,A2,b7),(r1,A2,b8),(r1,A2,b9),(r1,A2,b10),(r1,A2,b11),(r1,A2,b12),(r1,A2,b13),(r1,A2,b14),(r1,A2,b15),(r1,A2,b16),(r1,A2,b17),(r1,A2,b18),(r1,A2,b19),(r1,A2,b20),(r1,A2,b21),(r1,A2,b22),(r1,A2,b23),(r1,A2,b24),(r1,A2,b25),(r1,A2,b26),(r1,A2,b27),(r1,A2,b28),(r1,A2,b29),(r1,A2,b30),(r1,A2,b31),(r1,A2,b32),(r1,A2,b33),(r1,A2,b34),(r1,A2,b35),(r1,A2,b36),(r1,A2,b37),(r1,A2,b38),(r1,A2,b39),(r1,A2,b40),(r1,A2,b41),(r1,A2,b42),(r1,A2,b43),(r1,A2,b44),(r1,A2,b45),(r1,A2,b46),(r1,A2,b47),(r1,A2,b48),(r1,A2,b49),(r1,A2,b50),(r1,A2,b51),(r1,A2,b52),(r1,A2,b53),(r1,A2,b54),(r1,A2,b55),(r1,A2,b56),(r1,A2,b57),(r1,A2,b58),(r1,A2,b59),(r1,A2,b60),(r1,A2,b61),(r1,A2,b62),(r1,A2,b63),(r1,A2,b64),(r1,A2,b65),(r1,A2,b66),(r1,A2,b67),(r1,A2,b68),(r1,A2,b69),(r1,A2,b70),(r1,A2,b71),(r1,A2,b72),(r1,A2,b73),(r1,A2,b74),(r1,A2,b75),(r1,A2,b76),(r1,A2,b77),(r1,A2,b78),(r1,A2,b79),(r1,A2,b80),(r1,A2,b81),(r1,A2,b82),(r1,A2,b83),(r1,A2,b84),(r1,A2,b85),(r1,A2,b86),(r1,A2,b87),(r1,A2,b88),(r1,A2,b89),(r1,A2,b90),(r1,A2,b91),(r1,A2,b92),(r1,A2,b93),(r1,A2,b94),(r1,A2,b95),(r1,A2,b96),(r1,A2,b97),(r1,A2,b98),(r1,A2,b99),(r1,A2,b100),(r1,A2,b101),(r1,A2,b102),(r1,A2,b103),(r1,A2,b104),(r1,A2,b105),(r1,A2,b106),(r1,A2,b107),(r1,A2,b108),(r1,A2,b109),(r1,A2,b110),(r1,A2,b111),(r1,A2,b112),(r1,A2,b113),(r1,A2,b114),(r1,A2,b115),(r1,A2,b116),(r1,A2,b117),(r1,A2,b118),(r1,A2,b119),(r1,A2,b120),(r1,A2,b121),(r1,A2,b122),(r1,A2,b123),(r1,A2,b124),(r1,A2,b125),(r1,A2,b126),(r1,A2,b127),(r1,A2,b128),(r1,A2,b129),(r1,A2,b130),(r1,A2,b131),(r1,A2,b132),(r1,A2,b133),(r1,A2,b134),(r1,A3,b1),(r1,A3,b2),(r1,A3,b3),(r1,A3,b4),(r1,A3,b5),(r1,A3,b6),(r1,A3,b7),(r1,A3,b8),(r1,A3,b9),(r1,A3,b10),(r1,A3,b11),(r1,A3,b12),(r1,A3,b13),(r1,A3,b14),(r1,A3,b15),(r1,A3,b16),(r1,A3,b17),(r1,A3,b18),(r1,A3,b19),(r1,A3,b20),(r1,A3,b21),(r1,A3,b22),(r1,A3,b23),(r1,A3,b24),(r1,A3,b25),(r1,A3,b26),(r1,A3,b27),(r1,A3,b28),(r1,A3,b29),(r1,A3,b30),(r1,A3,b31),(r1,A3,b32),(r1,A3,b33),(r1,A3,b34),(r1,A3,b35),(r1,A3,b36),(r1,A3,b37),(r1,A3,b38),(r1,A3,b39),(r1,A3,b40),(r1,A3,b41),(r1,A3,b42),(r1,A3,b43),(r1,A3,b44),(r1,A3,b45),(r1,A3,b46),(r1,A3,b47),(r1,A3,b48),(r1,A3,b49),(r1,A3,b50),(r1,A3,b51),(r1,A3,b52),(r1,A3,b53),(r1,A3,b54),(r1,A3,b55),(r1,A3,b56),(r1,A3,b57),(r1,A3,b58),(r1,A3,b59),(r1,A3,b60),(r1,A3,b61),(r1,A3,b62),(r1,A3,b63),(r1,A3,b64),(r1,A3,b65),(r1,A3,b66),(r1,A3,b67),(r1,A3,b68),(r1,A3,b69),(r1,A3,b70),(r1,A3,b71),(r1,A3,b72),(r1,A3,b73),(r1,A3,b74),(r1,A3,b75),(r1,A3,b76),(r1,A3,b77),(r1,A3,b78),(r1,A3,b79),(r1,A3,b80),(r1,A3,b81),(r1,A3,b82),(r1,A3,b83),(r1,A3,b84),(r1,A3,b85),(r1,A3,b86),(r1,A3,b87),(r1,A3,b88),(r1,A3,b89),(r1,A3,b90),(r1,A3,b91),(r1,A3,b92),(r1,A3,b93),(r1,A3,b94),(r1,A3,b95),(r1,A3,b96),(r1,A3,b97),(r1,A3,b98),(r1,A3,b99),(r1,A3,b100),(r1,A3,b101),(r1,A3,b102),(r1,A3,b103),(r1,A3,b104),(r1,A3,b105),(r1,A3,b106),(r1,A3,b107),(r1,A3,b108),(r1,A3,b109),(r1,A3,b110),(r1,A3,b111),(r1,A3,b112),(r1,A3,b113),(r1,A3,b114),(r1,A3,b115),(r1,A3,b116),(r1,A3,b117),(r1,A3,b118),(r1,A3,b119),(r1,A3,b120),(r1,A3,b121),(r1,A3,b122),(r1,A3,b123),(r1,A3,b124),(r1,A3,b125),(r1,A3,b126),(r1,A3,b127),(r1,A3,b128),(r1,A3,b129),(r1,A3,b130),(r1,A3,b131),(r1,A3,b132),(r1,A3,b133),(r1,A3,b134),(r1,A4,b1),(r1,A4,b2),(r1,A4,b3),(r1,A4,b4),(r1,A4,b5),(r1,A4,b6),(r1,A4,b7),(r1,A4,b8),(r1,A4,b9),(r1,A4,b10),(r1,A4,b11),(r1,A4,b12),(r1,A4,b13),(r1,A4,b14),(r1,A4,b15),(r1,A4,b16),(r1,A4,b17),(r1,A4,b18),(r1,A4,b19),(r1,A4,b20),(r1,A4,b21),(r1,A4,b22),(r1,A4,b23),(r1,A4,b24),(r1,A4,b25),(r1,A4,b26),(r1,A4,b27),(r1,A4,b28),(r1,A4,b29),(r1,A4,b30),(r1,A4,b31),(r1,A4,b32),(r1,A4,b33),(r1,A4,b34),(r1,A4,b35),(r1,A4,b36),(r1,A4,b37),(r1,A4,b38),(r1,A4,b39),(r1,A4,b40),(r1,A4,b41),(r1,A4,b42),(r1,A4,b43),(r1,A4,b44),(r1,A4,b45),(r1,A4,b46),(r1,A4,b47),(r1,A4,b48),(r1,A4,b49),(r1,A4,b50),(r1,A4,b51),(r1,A4,b52),(r1,A4,b53),(r1,A4,b54),(r1,A4,b55),(r1,A4,b56),(r1,A4,b57),(r1,A4,b58),(r1,A4,b59),(r1,A4,b60),(r1,A4,b61),(r1,A4,b62),(r1,A4,b63),(r1,A4,b64),(r1,A4,b65),(r1,A4,b66),(r1,A4,b67),(r1,A4,b68),(r1,A4,b69),(r1,A4,b70),(r1,A4,b71),(r1,A4,b72),(r1,A4,b73),(r1,A4,b74),(r1,A4,b75),(r1,A4,b76),(r1,A4,b77),(r1,A4,b78),(r1,A4,b79),(r1,A4,b80),(r1,A4,b81),(r1,A4,b82),(r1,A4,b83),(r1,A4,b84),(r1,A4,b85),(r1,A4,b86),(r1,A4,b87),(r1,A4,b88),(r1,A4,b89),(r1,A4,b90),(r1,A4,b91),(r1,A4,b92),(r1,A4,b93),(r1,A4,b94),(r1,A4,b95),(r1,A4,b96),(r1,A4,b97),(r1,A4,b98),(r1,A4,b99),(r1,A4,b100),(r1,A4,b101),(r1,A4,b102),(r1,A4,b103),(r1,A4,b104),(r1,A4,b105),(r1,A4,b106),(r1,A4,b107),(r1,A4,b108),(r1,A4,b109),(r1,A4,b110),(r1,A4,b111),(r1,A4,b112),(r1,A4,b113),(r1,A4,b114),(r1,A4,b115),(r1,A4,b116),(r1,A4,b117),(r1,A4,b118),(r1,A4,b119),(r1,A4,b120),(r1,A4,b121),(r1,A4,b122),(r1,A4,b123),(r1,A4,b124),(r1,A4,b125),(r1,A4,b126),(r1,A4,b127),(r1,A4,b128),(r1,A4,b129),(r1,A4,b130),(r1,A4,b131),(r1,A4,b132),(r1,A4,b133),(r1,A4,b134),(r2,A1,b1),(r2,A1,b2),(r2,A1,b3),(r2,A1,b4),(r2,A1,b5),(r2,A1,b6),(r2,A1,b7),(r2,A1,b8),(r2,A1,b9),(r2,A1,b10),(r2,A1,b11),(r2,A1,b12),(r2,A1,b13),(r2,A1,b14),(r2,A1,b15),(r2,A1,b16),(r2,A1,b17),(r2,A1,b18),(r2,A1,b19),(r2,A1,b20),(r2,A1,b21),(r2,A1,b22),(r2,A1,b23),(r2,A1,b24),(r2,A1,b25),(r2,A1,b26),(r2,A1,b27),(r2,A1,b28),(r2,A1,b29),(r2,A1,b30),(r2,A1,b31),(r2,A1,b32),(r2,A1,b33),(r2,A1,b34),(r2,A1,b35),(r2,A1,b36),(r2,A1,b37),(r2,A1,b38),(r2,A1,b39),(r2,A1,b40),(r2,A1,b41),(r2,A1,b42),(r2,A1,b43),(r2,A1,b44),(r2,A1,b45),(r2,A1,b46),(r2,A1,b47),(r2,A1,b48),(r2,A1,b49),(r2,A1,b50),(r2,A1,b51),(r2,A1,b52),(r2,A1,b53),(r2,A1,b54),(r2,A1,b55),(r2,A1,b56),(r2,A1,b57),(r2,A1,b58),(r2,A1,b59),(r2,A1,b60),(r2,A1,b61),(r2,A1,b62),(r2,A1,b63),(r2,A1,b64),(r2,A1,b65),(r2,A1,b66),(r2,A1,b67),(r2,A1,b68),(r2,A1,b69),(r2,A1,b70),(r2,A1,b71),(r2,A1,b72),(r2,A1,b73),(r2,A1,b74),(r2,A1,b75),(r2,A1,b76),(r2,A1,b77),(r2,A1,b78),(r2,A1,b79),(r2,A1,b80),(r2,A1,b81),(r2,A1,b82),(r2,A1,b83),(r2,A1,b84),(r2,A1,b85),(r2,A1,b86),(r2,A1,b87),(r2,A1,b88),(r2,A1,b89),(r2,A1,b90),(r2,A1,b91),(r2,A1,b92),(r2,A1,b93),(r2,A1,b94),(r2,A1,b95),(r2,A1,b96),(r2,A1,b97),(r2,A1,b98),(r2,A1,b99),(r2,A1,b100),(r2,A1,b101),(r2,A1,b102),(r2,A1,b103),(r2,A1,b104),(r2,A1,b105),(r2,A1,b106),(r2,A1,b107),(r2,A1,b108),(r2,A1,b109),(r2,A1,b110),(r2,A1,b111),(r2,A1,b112),(r2,A1,b113),(r2,A1,b114),(r2,A1,b115),(r2,A1,b116),(r2,A1,b117),(r2,A1,b118),(r2,A1,b119),(r2,A1,b120),(r2,A1,b121),(r2,A1,b122),(r2,A1,b123),(r2,A1,b124),(r2,A1,b125),(r2,A1,b126),(r2,A1,b127),(r2,A1,b128),(r2,A1,b129),(r2,A1,b130),(r2,A1,b131),(r2,A1,b132),(r2,A1,b133),(r2,A1,b134),(r2,A2,b1),(r2,A2,b2),(r2,A2,b3),(r2,A2,b4),(r2,A2,b5),(r2,A2,b6),(r2,A2,b7),(r2,A2,b8),(r2,A2,b9),(r2,A2,b10),(r2,A2,b11),(r2,A2,b12),(r2,A2,b13),(r2,A2,b14),(r2,A2,b15),(r2,A2,b16),(r2,A2,b17),(r2,A2,b18),(r2,A2,b19),(r2,A2,b20),(r2,A2,b21),(r2,A2,b22),(r2,A2,b23),(r2,A2,b24),(r2,A2,b25),(r2,A2,b26),(r2,A2,b27),(r2,A2,b28),(r2,A2,b29),(r2,A2,b30),(r2,A2,b31),(r2,A2,b32),(r2,A2,b33),(r2,A2,b34),(r2,A2,b35),(r2,A2,b36),(r2,A2,b37),(r2,A2,b38),(r2,A2,b39),(r2,A2,b40),(r2,A2,b41),(r2,A2,b42),(r2,A2,b43),(r2,A2,b44),(r2,A2,b45),(r2,A2,b46),(r2,A2,b47),(r2,A2,b48),(r2,A2,b49),(r2,A2,b50),(r2,A2,b51),(r2,A2,b52),(r2,A2,b53),(r2,A2,b54),(r2,A2,b55),(r2,A2,b56),(r2,A2,b57),(r2,A2,b58),(r2,A2,b59),(r2,A2,b60),(r2,A2,b61),(r2,A2,b62),(r2,A2,b63),(r2,A2,b64),(r2,A2,b65),(r2,A2,b66),(r2,A2,b67),(r2,A2,b68),(r2,A2,b69),(r2,A2,b70),(r2,A2,b71),(r2,A2,b72),(r2,A2,b73),(r2,A2,b74),(r2,A2,b75),(r2,A2,b76),(r2,A2,b77),(r2,A2,b78),(r2,A2,b79),(r2,A2,b80),(r2,A2,b81),(r2,A2,b82),(r2,A2,b83),(r2,A2,b84),(r2,A2,b85),(r2,A2,b86),(r2,A2,b87),(r2,A2,b88),(r2,A2,b89),(r2,A2,b90),(r2,A2,b91),(r2,A2,b92),(r2,A2,b93),(r2,A2,b94),(r2,A2,b95),(r2,A2,b96),(r2,A2,b97),(r2,A2,b98),(r2,A2,b99),(r2,A2,b100),(r2,A2,b101),(r2,A2,b102),(r2,A2,b103),(r2,A2,b104),(r2,A2,b105),(r2,A2,b106),(r2,A2,b107),(r2,A2,b108),(r2,A2,b109),(r2,A2,b110),(r2,A2,b111),(r2,A2,b112),(r2,A2,b113),(r2,A2,b114),(r2,A2,b115),(r2,A2,b116),(r2,A2,b117),(r2,A2,b118),(r2,A2,b119),(r2,A2,b120),(r2,A2,b121),(r2,A2,b122),(r2,A2,b123),(r2,A2,b124),(r2,A2,b125),(r2,A2,b126),(r2,A2,b127),(r2,A2,b128),(r2,A2,b129),(r2,A2,b130),(r2,A2,b131),(r2,A2,b132),(r2,A2,b133),(r2,A2,b134),(r2,A3,b1),(r2,A3,b2),(r2,A3,b3),(r2,A3,b4),(r2,A3,b5),(r2,A3,b6),(r2,A3,b7),(r2,A3,b8),(r2,A3,b9),(r2,A3,b10),(r2,A3,b11),(r2,A3,b12),(r2,A3,b13),(r2,A3,b14),(r2,A3,b15),(r2,A3,b16),(r2,A3,b17),(r2,A3,b18),(r2,A3,b19),(r2,A3,b20),(r2,A3,b21),(r2,A3,b22),(r2,A3,b23),(r2,A3,b24),(r2,A3,b25),(r2,A3,b26),(r2,A3,b27),(r2,A3,b28),(r2,A3,b29),(r2,A3,b30),(r2,A3,b31),(r2,A3,b32),(r2,A3,b33),(r2,A3,b34),(r2,A3,b35),(r2,A3,b36),(r2,A3,b37),(r2,A3,b38),(r2,A3,b39),(r2,A3,b40),(r2,A3,b41),(r2,A3,b42),(r2,A3,b43),(r2,A3,b44),(r2,A3,b45),(r2,A3,b46),(r2,A3,b47),(r2,A3,b48),(r2,A3,b49),(r2,A3,b50),(r2,A3,b51),(r2,A3,b52),(r2,A3,b53),(r2,A3,b54),(r2,A3,b55),(r2,A3,b56),(r2,A3,b57),(r2,A3,b58),(r2,A3,b59),(r2,A3,b60),(r2,A3,b61),(r2,A3,b62),(r2,A3,b63),(r2,A3,b64),(r2,A3,b65),(r2,A3,b66),(r2,A3,b67),(r2,A3,b68),(r2,A3,b69),(r2,A3,b70),(r2,A3,b71),(r2,A3,b72),(r2,A3,b73),(r2,A3,b74),(r2,A3,b75),(r2,A3,b76),(r2,A3,b77),(r2,A3,b78),(r2,A3,b79),(r2,A3,b80),(r2,A3,b81),(r2,A3,b82),(r2,A3,b83),(r2,A3,b84),(r2,A3,b85),(r2,A3,b86),(r2,A3,b87),(r2,A3,b88),(r2,A3,b89),(r2,A3,b90),(r2,A3,b91),(r2,A3,b92),(r2,A3,b93),(r2,A3,b94),(r2,A3,b95),(r2,A3,b96),(r2,A3,b97),(r2,A3,b98),(r2,A3,b99),(r2,A3,b100),(r2,A3,b101),(r2,A3,b102),(r2,A3,b103),(r2,A3,b104),(r2,A3,b105),(r2,A3,b106),(r2,A3,b107),(r2,A3,b108),(r2,A3,b109),(r2,A3,b110),(r2,A3,b111),(r2,A3,b112),(r2,A3,b113),(r2,A3,b114),(r2,A3,b115),(r2,A3,b116),(r2,A3,b117),(r2,A3,b118),(r2,A3,b119),(r2,A3,b120),(r2,A3,b121),(r2,A3,b122),(r2,A3,b123),(r2,A3,b124),(r2,A3,b125),(r2,A3,b126),(r2,A3,b127),(r2,A3,b128),(r2,A3,b129),(r2,A3,b130),(r2,A3,b131),(r2,A3,b132),(r2,A3,b133),(r2,A3,b134),(r2,A4,b1),(r2,A4,b2),(r2,A4,b3),(r2,A4,b4),(r2,A4,b5),(r2,A4,b6),(r2,A4,b7),(r2,A4,b8),(r2,A4,b9),(r2,A4,b10),(r2,A4,b11),(r2,A4,b12),(r2,A4,b13),(r2,A4,b14),(r2,A4,b15),(r2,A4,b16),(r2,A4,b17),(r2,A4,b18),(r2,A4,b19),(r2,A4,b20),(r2,A4,b21),(r2,A4,b22),(r2,A4,b23),(r2,A4,b24),(r2,A4,b25),(r2,A4,b26),(r2,A4,b27),(r2,A4,b28),(r2,A4,b29),(r2,A4,b30),(r2,A4,b31),(r2,A4,b32),(r2,A4,b33),(r2,A4,b34),(r2,A4,b35),(r2,A4,b36),(r2,A4,b37),(r2,A4,b38),(r2,A4,b39),(r2,A4,b40),(r2,A4,b41),(r2,A4,b42),(r2,A4,b43),(r2,A4,b44),(r2,A4,b45),(r2,A4,b46),(r2,A4,b47),(r2,A4,b48),(r2,A4,b49),(r2,A4,b50),(r2,A4,b51),(r2,A4,b52),(r2,A4,b53),(r2,A4,b54),(r2,A4,b55),(r2,A4,b56),(r2,A4,b57),(r2,A4,b58),(r2,A4,b59),(r2,A4,b60),(r2,A4,b61),(r2,A4,b62),(r2,A4,b63),(r2,A4,b64),(r2,A4,b65),(r2,A4,b66),(r2,A4,b67),(r2,A4,b68),(r2,A4,b69),(r2,A4,b70),(r2,A4,b71),(r2,A4,b72),(r2,A4,b73),(r2,A4,b74),(r2,A4,b75),(r2,A4,b76),(r2,A4,b77),(r2,A4,b78),(r2,A4,b79),(r2,A4,b80),(r2,A4,b81),(r2,A4,b82),(r2,A4,b83),(r2,A4,b84),(r2,A4,b85),(r2,A4,b86),(r2,A4,b87),(r2,A4,b88),(r2,A4,b89),(r2,A4,b90),(r2,A4,b91),(r2,A4,b92),(r2,A4,b93),(r2,A4,b94),(r2,A4,b95),(r2,A4,b96),(r2,A4,b97),(r2,A4,b98),(r2,A4,b99),(r2,A4,b100),(r2,A4,b101),(r2,A4,b102),(r2,A4,b103),(r2,A4,b104),(r2,A4,b105),(r2,A4,b106),(r2,A4,b107),(r2,A4,b108),(r2,A4,b109),(r2,A4,b110),(r2,A4,b111),(r2,A4,b112),(r2,A4,b113),(r2,A4,b114),(r2,A4,b115),(r2,A4,b116),(r2,A4,b117),(r2,A4,b118),(r2,A4,b119),(r2,A4,b120),(r2,A4,b121),(r2,A4,b122),(r2,A4,b123),(r2,A4,b124),(r2,A4,b125),(r2,A4,b126),(r2,A4,b127),(r2,A4,b128),(r2,A4,b129),(r2,A4,b130),(r2,A4,b131),(r2,A4,b132),(r2,A4,b133),(r2,A4,b134),(r3,A1,b1),(r3,A1,b2),(r3,A1,b3),(r3,A1,b4),(r3,A1,b5),(r3,A1,b6),(r3,A1,b7),(r3,A1,b8),(r3,A1,b9),(r3,A1,b10),(r3,A1,b11),(r3,A1,b12),(r3,A1,b13),(r3,A1,b14),(r3,A1,b15),(r3,A1,b16),(r3,A1,b17),(r3,A1,b18),(r3,A1,b19),(r3,A1,b20),(r3,A1,b21),(r3,A1,b22),(r3,A1,b23),(r3,A1,b24),(r3,A1,b25),(r3,A1,b26),(r3,A1,b27),(r3,A1,b28),(r3,A1,b29),(r3,A1,b30),(r3,A1,b31),(r3,A1,b32),(r3,A1,b33),(r3,A1,b34),(r3,A1,b35),(r3,A1,b36),(r3,A1,b37),(r3,A1,b38),(r3,A1,b39),(r3,A1,b40),(r3,A1,b41),(r3,A1,b42),(r3,A1,b43),(r3,A1,b44),(r3,A1,b45),(r3,A1,b46),(r3,A1,b47),(r3,A1,b48),(r3,A1,b49),(r3,A1,b50),(r3,A1,b51),(r3,A1,b52),(r3,A1,b53),(r3,A1,b54),(r3,A1,b55),(r3,A1,b56),(r3,A1,b57),(r3,A1,b58),(r3,A1,b59),(r3,A1,b60),(r3,A1,b61),(r3,A1,b62),(r3,A1,b63),(r3,A1,b64),(r3,A1,b65),(r3,A1,b66),(r3,A1,b67),(r3,A1,b68),(r3,A1,b69),(r3,A1,b70),(r3,A1,b71),(r3,A1,b72),(r3,A1,b73),(r3,A1,b74),(r3,A1,b75),(r3,A1,b76),(r3,A1,b77),(r3,A1,b78),(r3,A1,b79),(r3,A1,b80),(r3,A1,b81),(r3,A1,b82),(r3,A1,b83),(r3,A1,b84),(r3,A1,b85),(r3,A1,b86),(r3,A1,b87),(r3,A1,b88),(r3,A1,b89),(r3,A1,b90),(r3,A1,b91),(r3,A1,b92),(r3,A1,b93),(r3,A1,b94),(r3,A1,b95),(r3,A1,b96),(r3,A1,b97),(r3,A1,b98),(r3,A1,b99),(r3,A1,b100),(r3,A1,b101),(r3,A1,b102),(r3,A1,b103),(r3,A1,b104),(r3,A1,b105),(r3,A1,b106),(r3,A1,b107),(r3,A1,b108),(r3,A1,b109),(r3,A1,b110),(r3,A1,b111),(r3,A1,b112),(r3,A1,b113),(r3,A1,b114),(r3,A1,b115),(r3,A1,b116),(r3,A1,b117),(r3,A1,b118),(r3,A1,b119),(r3,A1,b120),(r3,A1,b121),(r3,A1,b122),(r3,A1,b123),(r3,A1,b124),(r3,A1,b125),(r3,A1,b126),(r3,A1,b127),(r3,A1,b128),(r3,A1,b129),(r3,A1,b130),(r3,A1,b131),(r3,A1,b132),(r3,A1,b133),(r3,A1,b134),(r3,A2,b1),(r3,A2,b2),(r3,A2,b3),(r3,A2,b4),(r3,A2,b5),(r3,A2,b6),(r3,A2,b7),(r3,A2,b8),(r3,A2,b9),(r3,A2,b10),(r3,A2,b11),(r3,A2,b12),(r3,A2,b13),(r3,A2,b14),(r3,A2,b15),(r3,A2,b16),(r3,A2,b17),(r3,A2,b18),(r3,A2,b19),(r3,A2,b20),(r3,A2,b21),(r3,A2,b22),(r3,A2,b23),(r3,A2,b24),(r3,A2,b25),(r3,A2,b26),(r3,A2,b27),(r3,A2,b28),(r3,A2,b29),(r3,A2,b30),(r3,A2,b31),(r3,A2,b32),(r3,A2,b33),(r3,A2,b34),(r3,A2,b35),(r3,A2,b36),(r3,A2,b37),(r3,A2,b38),(r3,A2,b39),(r3,A2,b40),(r3,A2,b41),(r3,A2,b42),(r3,A2,b43),(r3,A2,b44),(r3,A2,b45),(r3,A2,b46),(r3,A2,b47),(r3,A2,b48),(r3,A2,b49),(r3,A2,b50),(r3,A2,b51),(r3,A2,b52),(r3,A2,b53),(r3,A2,b54),(r3,A2,b55),(r3,A2,b56),(r3,A2,b57),(r3,A2,b58),(r3,A2,b59),(r3,A2,b60),(r3,A2,b61),(r3,A2,b62),(r3,A2,b63),(r3,A2,b64),(r3,A2,b65),(r3,A2,b66),(r3,A2,b67),(r3,A2,b68),(r3,A2,b69),(r3,A2,b70),(r3,A2,b71),(r3,A2,b72),(r3,A2,b73),(r3,A2,b74),(r3,A2,b75),(r3,A2,b76),(r3,A2,b77),(r3,A2,b78),(r3,A2,b79),(r3,A2,b80),(r3,A2,b81),(r3,A2,b82),(r3,A2,b83),(r3,A2,b84),(r3,A2,b85),(r3,A2,b86),(r3,A2,b87),(r3,A2,b88),(r3,A2,b89),(r3,A2,b90),(r3,A2,b91),(r3,A2,b92),(r3,A2,b93),(r3,A2,b94),(r3,A2,b95),(r3,A2,b96),(r3,A2,b97),(r3,A2,b98),(r3,A2,b99),(r3,A2,b100),(r3,A2,b101),(r3,A2,b102),(r3,A2,b103),(r3,A2,b104),(r3,A2,b105),(r3,A2,b106),(r3,A2,b107),(r3,A2,b108),(r3,A2,b109),(r3,A2,b110),(r3,A2,b111),(r3,A2,b112),(r3,A2,b113),(r3,A2,b114),(r3,A2,b115),(r3,A2,b116),(r3,A2,b117),(r3,A2,b118),(r3,A2,b119),(r3,A2,b120),(r3,A2,b121),(r3,A2,b122),(r3,A2,b123),(r3,A2,b124),(r3,A2,b125),(r3,A2,b126),(r3,A2,b127),(r3,A2,b128),(r3,A2,b129),(r3,A2,b130),(r3,A2,b131),(r3,A2,b132),(r3,A2,b133),(r3,A2,b134),(r3,A3,b1),(r3,A3,b2),(r3,A3,b3),(r3,A3,b4),(r3,A3,b5),(r3,A3,b6),(r3,A3,b7),(r3,A3,b8),(r3,A3,b9),(r3,A3,b10),(r3,A3,b11),(r3,A3,b12),(r3,A3,b13),(r3,A3,b14),(r3,A3,b15),(r3,A3,b16),(r3,A3,b17),(r3,A3,b18),(r3,A3,b19),(r3,A3,b20),(r3,A3,b21),(r3,A3,b22),(r3,A3,b23),(r3,A3,b24),(r3,A3,b25),(r3,A3,b26),(r3,A3,b27),(r3,A3,b28),(r3,A3,b29),(r3,A3,b30),(r3,A3,b31),(r3,A3,b32),(r3,A3,b33),(r3,A3,b34),(r3,A3,b35),(r3,A3,b36),(r3,A3,b37),(r3,A3,b38),(r3,A3,b39),(r3,A3,b40),(r3,A3,b41),(r3,A3,b42),(r3,A3,b43),(r3,A3,b44),(r3,A3,b45),(r3,A3,b46),(r3,A3,b47),(r3,A3,b48),(r3,A3,b49),(r3,A3,b50),(r3,A3,b51),(r3,A3,b52),(r3,A3,b53),(r3,A3,b54),(r3,A3,b55),(r3,A3,b56),(r3,A3,b57),(r3,A3,b58),(r3,A3,b59),(r3,A3,b60),(r3,A3,b61),(r3,A3,b62),(r3,A3,b63),(r3,A3,b64),(r3,A3,b65),(r3,A3,b66),(r3,A3,b67),(r3,A3,b68),(r3,A3,b69),(r3,A3,b70),(r3,A3,b71),(r3,A3,b72),(r3,A3,b73),(r3,A3,b74),(r3,A3,b75),(r3,A3,b76),(r3,A3,b77),(r3,A3,b78),(r3,A3,b79),(r3,A3,b80),(r3,A3,b81),(r3,A3,b82),(r3,A3,b83),(r3,A3,b84),(r3,A3,b85),(r3,A3,b86),(r3,A3,b87),(r3,A3,b88),(r3,A3,b89),(r3,A3,b90),(r3,A3,b91),(r3,A3,b92),(r3,A3,b93),(r3,A3,b94),(r3,A3,b95),(r3,A3,b96),(r3,A3,b97),(r3,A3,b98),(r3,A3,b99),(r3,A3,b100),(r3,A3,b101),(r3,A3,b102),(r3,A3,b103),(r3,A3,b104),(r3,A3,b105),(r3,A3,b106),(r3,A3,b107),(r3,A3,b108),(r3,A3,b109),(r3,A3,b110),(r3,A3,b111),(r3,A3,b112),(r3,A3,b113),(r3,A3,b114),(r3,A3,b115),(r3,A3,b116),(r3,A3,b117),(r3,A3,b118),(r3,A3,b119),(r3,A3,b120),(r3,A3,b121),(r3,A3,b122),(r3,A3,b123),(r3,A3,b124),(r3,A3,b125),(r3,A3,b126),(r3,A3,b127),(r3,A3,b128),(r3,A3,b129),(r3,A3,b130),(r3,A3,b131),(r3,A3,b132),(r3,A3,b133),(r3,A3,b134),(r3,A4,b1),(r3,A4,b2),(r3,A4,b3),(r3,A4,b4),(r3,A4,b5),(r3,A4,b6),(r3,A4,b7),(r3,A4,b8),(r3,A4,b9),(r3,A4,b10),(r3,A4,b11),(r3,A4,b12),(r3,A4,b13),(r3,A4,b14),(r3,A4,b15),(r3,A4,b16),(r3,A4,b17),(r3,A4,b18),(r3,A4,b19),(r3,A4,b20),(r3,A4,b21),(r3,A4,b22),(r3,A4,b23),(r3,A4,b24),(r3,A4,b25),(r3,A4,b26),(r3,A4,b27),(r3,A4,b28),(r3,A4,b29),(r3,A4,b30),(r3,A4,b31),(r3,A4,b32),(r3,A4,b33),(r3,A4,b34),(r3,A4,b35),(r3,A4,b36),(r3,A4,b37),(r3,A4,b38),(r3,A4,b39),(r3,A4,b40),(r3,A4,b41),(r3,A4,b42),(r3,A4,b43),(r3,A4,b44),(r3,A4,b45),(r3,A4,b46),(r3,A4,b47),(r3,A4,b48),(r3,A4,b49),(r3,A4,b50),(r3,A4,b51),(r3,A4,b52),(r3,A4,b53),(r3,A4,b54),(r3,A4,b55),(r3,A4,b56),(r3,A4,b57),(r3,A4,b58),(r3,A4,b59),(r3,A4,b60),(r3,A4,b61),(r3,A4,b62),(r3,A4,b63),(r3,A4,b64),(r3,A4,b65),(r3,A4,b66),(r3,A4,b67),(r3,A4,b68),(r3,A4,b69),(r3,A4,b70),(r3,A4,b71),(r3,A4,b72),(r3,A4,b73),(r3,A4,b74),(r3,A4,b75),(r3,A4,b76),(r3,A4,b77),(r3,A4,b78),(r3,A4,b79),(r3,A4,b80),(r3,A4,b81),(r3,A4,b82),(r3,A4,b83),(r3,A4,b84),(r3,A4,b85),(r3,A4,b86),(r3,A4,b87),(r3,A4,b88),(r3,A4,b89),(r3,A4,b90),(r3,A4,b91),(r3,A4,b92),(r3,A4,b93),(r3,A4,b94),(r3,A4,b95),(r3,A4,b96),(r3,A4,b97),(r3,A4,b98),(r3,A4,b99),(r3,A4,b100),(r3,A4,b101),(r3,A4,b102),(r3,A4,b103),(r3,A4,b104),(r3,A4,b105),(r3,A4,b106),(r3,A4,b107),(r3,A4,b108),(r3,A4,b109),(r3,A4,b110),(r3,A4,b111),(r3,A4,b112),(r3,A4,b113),(r3,A4,b114),(r3,A4,b115),(r3,A4,b116),(r3,A4,b117),(r3,A4,b118),(r3,A4,b119),(r3,A4,b120),(r3,A4,b121),(r3,A4,b122),(r3,A4,b123),(r3,A4,b124),(r3,A4,b125),(r3,A4,b126),(r3,A4,b127),(r3,A4,b128),(r3,A4,b129),(r3,A4,b130),(r3,A4,b131),(r3,A4,b132),(r3,A4,b133),(r3,A4,b134),(r4,A1,b1),(r4,A1,b2),(r4,A1,b3),(r4,A1,b4),(r4,A1,b5),(r4,A1,b6),(r4,A1,b7),(r4,A1,b8),(r4,A1,b9),(r4,A1,b10),(r4,A1,b11),(r4,A1,b12),(r4,A1,b13),(r4,A1,b14),(r4,A1,b15),(r4,A1,b16),(r4,A1,b17),(r4,A1,b18),(r4,A1,b19),(r4,A1,b20),(r4,A1,b21),(r4,A1,b22),(r4,A1,b23),(r4,A1,b24),(r4,A1,b25),(r4,A1,b26),(r4,A1,b27),(r4,A1,b28),(r4,A1,b29),(r4,A1,b30),(r4,A1,b31),(r4,A1,b32),(r4,A1,b33),(r4,A1,b34),(r4,A1,b35),(r4,A1,b36),(r4,A1,b37),(r4,A1,b38),(r4,A1,b39),(r4,A1,b40),(r4,A1,b41),(r4,A1,b42),(r4,A1,b43),(r4,A1,b44),(r4,A1,b45),(r4,A1,b46),(r4,A1,b47),(r4,A1,b48),(r4,A1,b49),(r4,A1,b50),(r4,A1,b51),(r4,A1,b52),(r4,A1,b53),(r4,A1,b54),(r4,A1,b55),(r4,A1,b56),(r4,A1,b57),(r4,A1,b58),(r4,A1,b59),(r4,A1,b60),(r4,A1,b61),(r4,A1,b62),(r4,A1,b63),(r4,A1,b64),(r4,A1,b65),(r4,A1,b66),(r4,A1,b67),(r4,A1,b68),(r4,A1,b69),(r4,A1,b70),(r4,A1,b71),(r4,A1,b72),(r4,A1,b73),(r4,A1,b74),(r4,A1,b75),(r4,A1,b76),(r4,A1,b77),(r4,A1,b78),(r4,A1,b79),(r4,A1,b80),(r4,A1,b81),(r4,A1,b82),(r4,A1,b83),(r4,A1,b84),(r4,A1,b85),(r4,A1,b86),(r4,A1,b87),(r4,A1,b88),(r4,A1,b89),(r4,A1,b90),(r4,A1,b91),(r4,A1,b92),(r4,A1,b93),(r4,A1,b94),(r4,A1,b95),(r4,A1,b96),(r4,A1,b97),(r4,A1,b98),(r4,A1,b99),(r4,A1,b100),(r4,A1,b101),(r4,A1,b102),(r4,A1,b103),(r4,A1,b104),(r4,A1,b105),(r4,A1,b106),(r4,A1,b107),(r4,A1,b108),(r4,A1,b109),(r4,A1,b110),(r4,A1,b111),(r4,A1,b112),(r4,A1,b113),(r4,A1,b114),(r4,A1,b115),(r4,A1,b116),(r4,A1,b117),(r4,A1,b118),(r4,A1,b119),(r4,A1,b120),(r4,A1,b121),(r4,A1,b122),(r4,A1,b123),(r4,A1,b124),(r4,A1,b125),(r4,A1,b126),(r4,A1,b127),(r4,A1,b128),(r4,A1,b129),(r4,A1,b130),(r4,A1,b131),(r4,A1,b132),(r4,A1,b133),(r4,A1,b134),(r4,A2,b1),(r4,A2,b2),(r4,A2,b3),(r4,A2,b4),(r4,A2,b5),(r4,A2,b6),(r4,A2,b7),(r4,A2,b8),(r4,A2,b9),(r4,A2,b10),(r4,A2,b11),(r4,A2,b12),(r4,A2,b13),(r4,A2,b14),(r4,A2,b15),(r4,A2,b16),(r4,A2,b17),(r4,A2,b18),(r4,A2,b19),(r4,A2,b20),(r4,A2,b21),(r4,A2,b22),(r4,A2,b23),(r4,A2,b24),(r4,A2,b25),(r4,A2,b26),(r4,A2,b27),(r4,A2,b28),(r4,A2,b29),(r4,A2,b30),(r4,A2,b31),(r4,A2,b32),(r4,A2,b33),(r4,A2,b34),(r4,A2,b35),(r4,A2,b36),(r4,A2,b37),(r4,A2,b38),(r4,A2,b39),(r4,A2,b40),(r4,A2,b41),(r4,A2,b42),(r4,A2,b43),(r4,A2,b44),(r4,A2,b45),(r4,A2,b46),(r4,A2,b47),(r4,A2,b48),(r4,A2,b49),(r4,A2,b50),(r4,A2,b51),(r4,A2,b52),(r4,A2,b53),(r4,A2,b54),(r4,A2,b55),(r4,A2,b56),(r4,A2,b57),(r4,A2,b58),(r4,A2,b59),(r4,A2,b60),(r4,A2,b61),(r4,A2,b62),(r4,A2,b63),(r4,A2,b64),(r4,A2,b65),(r4,A2,b66),(r4,A2,b67),(r4,A2,b68),(r4,A2,b69),(r4,A2,b70),(r4,A2,b71),(r4,A2,b72),(r4,A2,b73),(r4,A2,b74),(r4,A2,b75),(r4,A2,b76),(r4,A2,b77),(r4,A2,b78),(r4,A2,b79),(r4,A2,b80),(r4,A2,b81),(r4,A2,b82),(r4,A2,b83),(r4,A2,b84),(r4,A2,b85),(r4,A2,b86),(r4,A2,b87),(r4,A2,b88),(r4,A2,b89),(r4,A2,b90),(r4,A2,b91),(r4,A2,b92),(r4,A2,b93),(r4,A2,b94),(r4,A2,b95),(r4,A2,b96),(r4,A2,b97),(r4,A2,b98),(r4,A2,b99),(r4,A2,b100),(r4,A2,b101),(r4,A2,b102),(r4,A2,b103),(r4,A2,b104),(r4,A2,b105),(r4,A2,b106),(r4,A2,b107),(r4,A2,b108),(r4,A2,b109),(r4,A2,b110),(r4,A2,b111),(r4,A2,b112),(r4,A2,b113),(r4,A2,b114),(r4,A2,b115),(r4,A2,b116),(r4,A2,b117),(r4,A2,b118),(r4,A2,b119),(r4,A2,b120),(r4,A2,b121),(r4,A2,b122),(r4,A2,b123),(r4,A2,b124),(r4,A2,b125),(r4,A2,b126),(r4,A2,b127),(r4,A2,b128),(r4,A2,b129),(r4,A2,b130),(r4,A2,b131),(r4,A2,b132),(r4,A2,b133),(r4,A2,b134),(r4,A3,b1),(r4,A3,b2),(r4,A3,b3),(r4,A3,b4),(r4,A3,b5),(r4,A3,b6),(r4,A3,b7),(r4,A3,b8),(r4,A3,b9),(r4,A3,b10),(r4,A3,b11),(r4,A3,b12),(r4,A3,b13),(r4,A3,b14),(r4,A3,b15),(r4,A3,b16),(r4,A3,b17),(r4,A3,b18),(r4,A3,b19),(r4,A3,b20),(r4,A3,b21),(r4,A3,b22),(r4,A3,b23),(r4,A3,b24),(r4,A3,b25),(r4,A3,b26),(r4,A3,b27),(r4,A3,b28),(r4,A3,b29),(r4,A3,b30),(r4,A3,b31),(r4,A3,b32),(r4,A3,b33),(r4,A3,b34),(r4,A3,b35),(r4,A3,b36),(r4,A3,b37),(r4,A3,b38),(r4,A3,b39),(r4,A3,b40),(r4,A3,b41),(r4,A3,b42),(r4,A3,b43),(r4,A3,b44),(r4,A3,b45),(r4,A3,b46),(r4,A3,b47),(r4,A3,b48),(r4,A3,b49),(r4,A3,b50),(r4,A3,b51),(r4,A3,b52),(r4,A3,b53),(r4,A3,b54),(r4,A3,b55),(r4,A3,b56),(r4,A3,b57),(r4,A3,b58),(r4,A3,b59),(r4,A3,b60),(r4,A3,b61),(r4,A3,b62),(r4,A3,b63),(r4,A3,b64),(r4,A3,b65),(r4,A3,b66),(r4,A3,b67),(r4,A3,b68),(r4,A3,b69),(r4,A3,b70),(r4,A3,b71),(r4,A3,b72),(r4,A3,b73),(r4,A3,b74),(r4,A3,b75),(r4,A3,b76),(r4,A3,b77),(r4,A3,b78),(r4,A3,b79),(r4,A3,b80),(r4,A3,b81),(r4,A3,b82),(r4,A3,b83),(r4,A3,b84),(r4,A3,b85),(r4,A3,b86),(r4,A3,b87),(r4,A3,b88),(r4,A3,b89),(r4,A3,b90),(r4,A3,b91),(r4,A3,b92),(r4,A3,b93),(r4,A3,b94),(r4,A3,b95),(r4,A3,b96),(r4,A3,b97),(r4,A3,b98),(r4,A3,b99),(r4,A3,b100),(r4,A3,b101),(r4,A3,b102),(r4,A3,b103),(r4,A3,b104),(r4,A3,b105),(r4,A3,b106),(r4,A3,b107),(r4,A3,b108),(r4,A3,b109),(r4,A3,b110),(r4,A3,b111),(r4,A3,b112),(r4,A3,b113),(r4,A3,b114),(r4,A3,b115),(r4,A3,b116),(r4,A3,b117),(r4,A3,b118),(r4,A3,b119),(r4,A3,b120),(r4,A3,b121),(r4,A3,b122),(r4,A3,b123),(r4,A3,b124),(r4,A3,b125),(r4,A3,b126),(r4,A3,b127),(r4,A3,b128),(r4,A3,b129),(r4,A3,b130),(r4,A3,b131),(r4,A3,b132),(r4,A3,b133),(r4,A3,b134),(r4,A4,b1),(r4,A4,b2),(r4,A4,b3),(r4,A4,b4),(r4,A4,b5),(r4,A4,b6),(r4,A4,b7),(r4,A4,b8),(r4,A4,b9),(r4,A4,b10),(r4,A4,b11),(r4,A4,b12),(r4,A4,b13),(r4,A4,b14),(r4,A4,b15),(r4,A4,b16),(r4,A4,b17),(r4,A4,b18),(r4,A4,b19),(r4,A4,b20),(r4,A4,b21),(r4,A4,b22),(r4,A4,b23),(r4,A4,b24),(r4,A4,b25),(r4,A4,b26),(r4,A4,b27),(r4,A4,b28),(r4,A4,b29),(r4,A4,b30),(r4,A4,b31),(r4,A4,b32),(r4,A4,b33),(r4,A4,b34),(r4,A4,b35),(r4,A4,b36),(r4,A4,b37),(r4,A4,b38),(r4,A4,b39),(r4,A4,b40),(r4,A4,b41),(r4,A4,b42),(r4,A4,b43),(r4,A4,b44),(r4,A4,b45),(r4,A4,b46),(r4,A4,b47),(r4,A4,b48),(r4,A4,b49),(r4,A4,b50),(r4,A4,b51),(r4,A4,b52),(r4,A4,b53),(r4,A4,b54),(r4,A4,b55),(r4,A4,b56),(r4,A4,b57),(r4,A4,b58),(r4,A4,b59),(r4,A4,b60),(r4,A4,b61),(r4,A4,b62),(r4,A4,b63),(r4,A4,b64),(r4,A4,b65),(r4,A4,b66),(r4,A4,b67),(r4,A4,b68),(r4,A4,b69),(r4,A4,b70),(r4,A4,b71),(r4,A4,b72),(r4,A4,b73),(r4,A4,b74),(r4,A4,b75),(r4,A4,b76),(r4,A4,b77),(r4,A4,b78),(r4,A4,b79),(r4,A4,b80),(r4,A4,b81),(r4,A4,b82),(r4,A4,b83),(r4,A4,b84),(r4,A4,b85),(r4,A4,b86),(r4,A4,b87),(r4,A4,b88),(r4,A4,b89),(r4,A4,b90),(r4,A4,b91),(r4,A4,b92),(r4,A4,b93),(r4,A4,b94),(r4,A4,b95),(r4,A4,b96),(r4,A4,b97),(r4,A4,b98),(r4,A4,b99),(r4,A4,b100),(r4,A4,b101),(r4,A4,b102),(r4,A4,b103),(r4,A4,b104),(r4,A4,b105),(r4,A4,b106),(r4,A4,b107),(r4,A4,b108),(r4,A4,b109),(r4,A4,b110),(r4,A4,b111),(r4,A4,b112),(r4,A4,b113),(r4,A4,b114),(r4,A4,b115),(r4,A4,b116),(r4,A4,b117),(r4,A4,b118),(r4,A4,b119),(r4,A4,b120),(r4,A4,b121),(r4,A4,b122),(r4,A4,b123),(r4,A4,b124),(r4,A4,b125),(r4,A4,b126),(r4,A4,b127),(r4,A4,b128),(r4,A4,b129),(r4,A4,b130),(r4,A4,b131),(r4,A4,b132),(r4,A4,b133),(r4,A4,b134),(r5,A1,b1),(r5,A1,b2),(r5,A1,b3),(r5,A1,b4),(r5,A1,b5),(r5,A1,b6),(r5,A1,b7),(r5,A1,b8),(r5,A1,b9),(r5,A1,b10),(r5,A1,b11),(r5,A1,b12),(r5,A1,b13),(r5,A1,b14),(r5,A1,b15),(r5,A1,b16),(r5,A1,b17),(r5,A1,b18),(r5,A1,b19),(r5,A1,b20),(r5,A1,b21),(r5,A1,b22),(r5,A1,b23),(r5,A1,b24),(r5,A1,b25),(r5,A1,b26),(r5,A1,b27),(r5,A1,b28),(r5,A1,b29),(r5,A1,b30),(r5,A1,b31),(r5,A1,b32),(r5,A1,b33),(r5,A1,b34),(r5,A1,b35),(r5,A1,b36),(r5,A1,b37),(r5,A1,b38),(r5,A1,b39),(r5,A1,b40),(r5,A1,b41),(r5,A1,b42),(r5,A1,b43),(r5,A1,b44),(r5,A1,b45),(r5,A1,b46),(r5,A1,b47),(r5,A1,b48),(r5,A1,b49),(r5,A1,b50),(r5,A1,b51),(r5,A1,b52),(r5,A1,b53),(r5,A1,b54),(r5,A1,b55),(r5,A1,b56),(r5,A1,b57),(r5,A1,b58),(r5,A1,b59),(r5,A1,b60),(r5,A1,b61),(r5,A1,b62),(r5,A1,b63),(r5,A1,b64),(r5,A1,b65),(r5,A1,b66),(r5,A1,b67),(r5,A1,b68),(r5,A1,b69),(r5,A1,b70),(r5,A1,b71),(r5,A1,b72),(r5,A1,b73),(r5,A1,b74),(r5,A1,b75),(r5,A1,b76),(r5,A1,b77),(r5,A1,b78),(r5,A1,b79),(r5,A1,b80),(r5,A1,b81),(r5,A1,b82),(r5,A1,b83),(r5,A1,b84),(r5,A1,b85),(r5,A1,b86),(r5,A1,b87),(r5,A1,b88),(r5,A1,b89),(r5,A1,b90),(r5,A1,b91),(r5,A1,b92),(r5,A1,b93),(r5,A1,b94),(r5,A1,b95),(r5,A1,b96),(r5,A1,b97),(r5,A1,b98),(r5,A1,b99),(r5,A1,b100),(r5,A1,b101),(r5,A1,b102),(r5,A1,b103),(r5,A1,b104),(r5,A1,b105),(r5,A1,b106),(r5,A1,b107),(r5,A1,b108),(r5,A1,b109),(r5,A1,b110),(r5,A1,b111),(r5,A1,b112),(r5,A1,b113),(r5,A1,b114),(r5,A1,b115),(r5,A1,b116),(r5,A1,b117),(r5,A1,b118),(r5,A1,b119),(r5,A1,b120),(r5,A1,b121),(r5,A1,b122),(r5,A1,b123),(r5,A1,b124),(r5,A1,b125),(r5,A1,b126),(r5,A1,b127),(r5,A1,b128),(r5,A1,b129),(r5,A1,b130),(r5,A1,b131),(r5,A1,b132),(r5,A1,b133),(r5,A1,b134),(r5,A2,b1),(r5,A2,b2),(r5,A2,b3),(r5,A2,b4),(r5,A2,b5),(r5,A2,b6),(r5,A2,b7),(r5,A2,b8),(r5,A2,b9),(r5,A2,b10),(r5,A2,b11),(r5,A2,b12),(r5,A2,b13),(r5,A2,b14),(r5,A2,b15),(r5,A2,b16),(r5,A2,b17),(r5,A2,b18),(r5,A2,b19),(r5,A2,b20),(r5,A2,b21),(r5,A2,b22),(r5,A2,b23),(r5,A2,b24),(r5,A2,b25),(r5,A2,b26),(r5,A2,b27),(r5,A2,b28),(r5,A2,b29),(r5,A2,b30),(r5,A2,b31),(r5,A2,b32),(r5,A2,b33),(r5,A2,b34),(r5,A2,b35),(r5,A2,b36),(r5,A2,b37),(r5,A2,b38),(r5,A2,b39),(r5,A2,b40),(r5,A2,b41),(r5,A2,b42),(r5,A2,b43),(r5,A2,b44),(r5,A2,b45),(r5,A2,b46),(r5,A2,b47),(r5,A2,b48),(r5,A2,b49),(r5,A2,b50),(r5,A2,b51),(r5,A2,b52),(r5,A2,b53),(r5,A2,b54),(r5,A2,b55),(r5,A2,b56),(r5,A2,b57),(r5,A2,b58),(r5,A2,b59),(r5,A2,b60),(r5,A2,b61),(r5,A2,b62),(r5,A2,b63),(r5,A2,b64),(r5,A2,b65),(r5,A2,b66),(r5,A2,b67),(r5,A2,b68),(r5,A2,b69),(r5,A2,b70),(r5,A2,b71),(r5,A2,b72),(r5,A2,b73),(r5,A2,b74),(r5,A2,b75),(r5,A2,b76),(r5,A2,b77),(r5,A2,b78),(r5,A2,b79),(r5,A2,b80),(r5,A2,b81),(r5,A2,b82),(r5,A2,b83),(r5,A2,b84),(r5,A2,b85),(r5,A2,b86),(r5,A2,b87),(r5,A2,b88),(r5,A2,b89),(r5,A2,b90),(r5,A2,b91),(r5,A2,b92),(r5,A2,b93),(r5,A2,b94),(r5,A2,b95),(r5,A2,b96),(r5,A2,b97),(r5,A2,b98),(r5,A2,b99),(r5,A2,b100),(r5,A2,b101),(r5,A2,b102),(r5,A2,b103),(r5,A2,b104),(r5,A2,b105),(r5,A2,b106),(r5,A2,b107),(r5,A2,b108),(r5,A2,b109),(r5,A2,b110),(r5,A2,b111),(r5,A2,b112),(r5,A2,b113),(r5,A2,b114),(r5,A2,b115),(r5,A2,b116),(r5,A2,b117),(r5,A2,b118),(r5,A2,b119),(r5,A2,b120),(r5,A2,b121),(r5,A2,b122),(r5,A2,b123),(r5,A2,b124),(r5,A2,b125),(r5,A2,b126),(r5,A2,b127),(r5,A2,b128),(r5,A2,b129),(r5,A2,b130),(r5,A2,b131),(r5,A2,b132),(r5,A2,b133),(r5,A2,b134),(r5,A3,b1),(r5,A3,b2),(r5,A3,b3),(r5,A3,b4),(r5,A3,b5),(r5,A3,b6),(r5,A3,b7),(r5,A3,b8),(r5,A3,b9),(r5,A3,b10),(r5,A3,b11),(r5,A3,b12),(r5,A3,b13),(r5,A3,b14),(r5,A3,b15),(r5,A3,b16),(r5,A3,b17),(r5,A3,b18),(r5,A3,b19),(r5,A3,b20),(r5,A3,b21),(r5,A3,b22),(r5,A3,b23),(r5,A3,b24),(r5,A3,b25),(r5,A3,b26),(r5,A3,b27),(r5,A3,b28),(r5,A3,b29),(r5,A3,b30),(r5,A3,b31),(r5,A3,b32),(r5,A3,b33),(r5,A3,b34),(r5,A3,b35),(r5,A3,b36),(r5,A3,b37),(r5,A3,b38),(r5,A3,b39),(r5,A3,b40),(r5,A3,b41),(r5,A3,b42),(r5,A3,b43),(r5,A3,b44),(r5,A3,b45),(r5,A3,b46),(r5,A3,b47),(r5,A3,b48),(r5,A3,b49),(r5,A3,b50),(r5,A3,b51),(r5,A3,b52),(r5,A3,b53),(r5,A3,b54),(r5,A3,b55),(r5,A3,b56),(r5,A3,b57),(r5,A3,b58),(r5,A3,b59),(r5,A3,b60),(r5,A3,b61),(r5,A3,b62),(r5,A3,b63),(r5,A3,b64),(r5,A3,b65),(r5,A3,b66),(r5,A3,b67),(r5,A3,b68),(r5,A3,b69),(r5,A3,b70),(r5,A3,b71),(r5,A3,b72),(r5,A3,b73),(r5,A3,b74),(r5,A3,b75),(r5,A3,b76),(r5,A3,b77),(r5,A3,b78),(r5,A3,b79),(r5,A3,b80),(r5,A3,b81),(r5,A3,b82),(r5,A3,b83),(r5,A3,b84),(r5,A3,b85),(r5,A3,b86),(r5,A3,b87),(r5,A3,b88),(r5,A3,b89),(r5,A3,b90),(r5,A3,b91),(r5,A3,b92),(r5,A3,b93),(r5,A3,b94),(r5,A3,b95),(r5,A3,b96),(r5,A3,b97),(r5,A3,b98),(r5,A3,b99),(r5,A3,b100),(r5,A3,b101),(r5,A3,b102),(r5,A3,b103),(r5,A3,b104),(r5,A3,b105),(r5,A3,b106),(r5,A3,b107),(r5,A3,b108),(r5,A3,b109),(r5,A3,b110),(r5,A3,b111),(r5,A3,b112),(r5,A3,b113),(r5,A3,b114),(r5,A3,b115),(r5,A3,b116),(r5,A3,b117),(r5,A3,b118),(r5,A3,b119),(r5,A3,b120),(r5,A3,b121),(r5,A3,b122),(r5,A3,b123),(r5,A3,b124),(r5,A3,b125),(r5,A3,b126),(r5,A3,b127),(r5,A3,b128),(r5,A3,b129),(r5,A3,b130),(r5,A3,b131),(r5,A3,b132),(r5,A3,b133),(r5,A3,b134),(r5,A4,b1),(r5,A4,b2),(r5,A4,b3),(r5,A4,b4),(r5,A4,b5),(r5,A4,b6),(r5,A4,b7),(r5,A4,b8),(r5,A4,b9),(r5,A4,b10),(r5,A4,b11),(r5,A4,b12),(r5,A4,b13),(r5,A4,b14),(r5,A4,b15),(r5,A4,b16),(r5,A4,b17),(r5,A4,b18),(r5,A4,b19),(r5,A4,b20),(r5,A4,b21),(r5,A4,b22),(r5,A4,b23),(r5,A4,b24),(r5,A4,b25),(r5,A4,b26),(r5,A4,b27),(r5,A4,b28),(r5,A4,b29),(r5,A4,b30),(r5,A4,b31),(r5,A4,b32),(r5,A4,b33),(r5,A4,b34),(r5,A4,b35),(r5,A4,b36),(r5,A4,b37),(r5,A4,b38),(r5,A4,b39),(r5,A4,b40),(r5,A4,b41),(r5,A4,b42),(r5,A4,b43),(r5,A4,b44),(r5,A4,b45),(r5,A4,b46),(r5,A4,b47),(r5,A4,b48),(r5,A4,b49),(r5,A4,b50),(r5,A4,b51),(r5,A4,b52),(r5,A4,b53),(r5,A4,b54),(r5,A4,b55),(r5,A4,b56),(r5,A4,b57),(r5,A4,b58),(r5,A4,b59),(r5,A4,b60),(r5,A4,b61),(r5,A4,b62),(r5,A4,b63),(r5,A4,b64),(r5,A4,b65),(r5,A4,b66),(r5,A4,b67),(r5,A4,b68),(r5,A4,b69),(r5,A4,b70),(r5,A4,b71),(r5,A4,b72),(r5,A4,b73),(r5,A4,b74),(r5,A4,b75),(r5,A4,b76),(r5,A4,b77),(r5,A4,b78),(r5,A4,b79),(r5,A4,b80),(r5,A4,b81),(r5,A4,b82),(r5,A4,b83),(r5,A4,b84),(r5,A4,b85),(r5,A4,b86),(r5,A4,b87),(r5,A4,b88),(r5,A4,b89),(r5,A4,b90),(r5,A4,b91),(r5,A4,b92),(r5,A4,b93),(r5,A4,b94),(r5,A4,b95),(r5,A4,b96),(r5,A4,b97),(r5,A4,b98),(r5,A4,b99),(r5,A4,b100),(r5,A4,b101),(r5,A4,b102),(r5,A4,b103),(r5,A4,b104),(r5,A4,b105),(r5,A4,b106),(r5,A4,b107),(r5,A4,b108),(r5,A4,b109),(r5,A4,b110),(r5,A4,b111),(r5,A4,b112),(r5,A4,b113),(r5,A4,b114),(r5,A4,b115),(r5,A4,b116),(r5,A4,b117),(r5,A4,b118),(r5,A4,b119),(r5,A4,b120),(r5,A4,b121),(r5,A4,b122),(r5,A4,b123),(r5,A4,b124),(r5,A4,b125),(r5,A4,b126),(r5,A4,b127),(r5,A4,b128),(r5,A4,b129),(r5,A4,b130),(r5,A4,b131),(r5,A4,b132),(r5,A4,b133),(r5,A4,b134),(r6,A1,b1),(r6,A1,b2),(r6,A1,b3),(r6,A1,b4),(r6,A1,b5),(r6,A1,b6),(r6,A1,b7),(r6,A1,b8),(r6,A1,b9),(r6,A1,b10),(r6,A1,b11),(r6,A1,b12),(r6,A1,b13),(r6,A1,b14),(r6,A1,b15),(r6,A1,b16),(r6,A1,b17),(r6,A1,b18),(r6,A1,b19),(r6,A1,b20),(r6,A1,b21),(r6,A1,b22),(r6,A1,b23),(r6,A1,b24),(r6,A1,b25),(r6,A1,b26),(r6,A1,b27),(r6,A1,b28),(r6,A1,b29),(r6,A1,b30),(r6,A1,b31),(r6,A1,b32),(r6,A1,b33),(r6,A1,b34),(r6,A1,b35),(r6,A1,b36),(r6,A1,b37),(r6,A1,b38),(r6,A1,b39),(r6,A1,b40),(r6,A1,b41),(r6,A1,b42),(r6,A1,b43),(r6,A1,b44),(r6,A1,b45),(r6,A1,b46),(r6,A1,b47),(r6,A1,b48),(r6,A1,b49),(r6,A1,b50),(r6,A1,b51),(r6,A1,b52),(r6,A1,b53),(r6,A1,b54),(r6,A1,b55),(r6,A1,b56),(r6,A1,b57),(r6,A1,b58),(r6,A1,b59),(r6,A1,b60),(r6,A1,b61),(r6,A1,b62),(r6,A1,b63),(r6,A1,b64),(r6,A1,b65),(r6,A1,b66),(r6,A1,b67),(r6,A1,b68),(r6,A1,b69),(r6,A1,b70),(r6,A1,b71),(r6,A1,b72),(r6,A1,b73),(r6,A1,b74),(r6,A1,b75),(r6,A1,b76),(r6,A1,b77),(r6,A1,b78),(r6,A1,b79),(r6,A1,b80),(r6,A1,b81),(r6,A1,b82),(r6,A1,b83),(r6,A1,b84),(r6,A1,b85),(r6,A1,b86),(r6,A1,b87),(r6,A1,b88),(r6,A1,b89),(r6,A1,b90),(r6,A1,b91),(r6,A1,b92),(r6,A1,b93),(r6,A1,b94),(r6,A1,b95),(r6,A1,b96),(r6,A1,b97),(r6,A1,b98),(r6,A1,b99),(r6,A1,b100),(r6,A1,b101),(r6,A1,b102),(r6,A1,b103),(r6,A1,b104),(r6,A1,b105),(r6,A1,b106),(r6,A1,b107),(r6,A1,b108),(r6,A1,b109),(r6,A1,b110),(r6,A1,b111),(r6,A1,b112),(r6,A1,b113),(r6,A1,b114),(r6,A1,b115),(r6,A1,b116),(r6,A1,b117),(r6,A1,b118),(r6,A1,b119),(r6,A1,b120),(r6,A1,b121),(r6,A1,b122),(r6,A1,b123),(r6,A1,b124),(r6,A1,b125),(r6,A1,b126),(r6,A1,b127),(r6,A1,b128),(r6,A1,b129),(r6,A1,b130),(r6,A1,b131),(r6,A1,b132),(r6,A1,b133),(r6,A1,b134),(r6,A2,b1),(r6,A2,b2),(r6,A2,b3),(r6,A2,b4),(r6,A2,b5),(r6,A2,b6),(r6,A2,b7),(r6,A2,b8),(r6,A2,b9),(r6,A2,b10),(r6,A2,b11),(r6,A2,b12),(r6,A2,b13),(r6,A2,b14),(r6,A2,b15),(r6,A2,b16),(r6,A2,b17),(r6,A2,b18),(r6,A2,b19),(r6,A2,b20),(r6,A2,b21),(r6,A2,b22),(r6,A2,b23),(r6,A2,b24),(r6,A2,b25),(r6,A2,b26),(r6,A2,b27),(r6,A2,b28),(r6,A2,b29),(r6,A2,b30),(r6,A2,b31),(r6,A2,b32),(r6,A2,b33),(r6,A2,b34),(r6,A2,b35),(r6,A2,b36),(r6,A2,b37),(r6,A2,b38),(r6,A2,b39),(r6,A2,b40),(r6,A2,b41),(r6,A2,b42),(r6,A2,b43),(r6,A2,b44),(r6,A2,b45),(r6,A2,b46),(r6,A2,b47),(r6,A2,b48),(r6,A2,b49),(r6,A2,b50),(r6,A2,b51),(r6,A2,b52),(r6,A2,b53),(r6,A2,b54),(r6,A2,b55),(r6,A2,b56),(r6,A2,b57),(r6,A2,b58),(r6,A2,b59),(r6,A2,b60),(r6,A2,b61),(r6,A2,b62),(r6,A2,b63),(r6,A2,b64),(r6,A2,b65),(r6,A2,b66),(r6,A2,b67),(r6,A2,b68),(r6,A2,b69),(r6,A2,b70),(r6,A2,b71),(r6,A2,b72),(r6,A2,b73),(r6,A2,b74),(r6,A2,b75),(r6,A2,b76),(r6,A2,b77),(r6,A2,b78),(r6,A2,b79),(r6,A2,b80),(r6,A2,b81),(r6,A2,b82),(r6,A2,b83),(r6,A2,b84),(r6,A2,b85),(r6,A2,b86),(r6,A2,b87),(r6,A2,b88),(r6,A2,b89),(r6,A2,b90),(r6,A2,b91),(r6,A2,b92),(r6,A2,b93),(r6,A2,b94),(r6,A2,b95),(r6,A2,b96),(r6,A2,b97),(r6,A2,b98),(r6,A2,b99),(r6,A2,b100),(r6,A2,b101),(r6,A2,b102),(r6,A2,b103),(r6,A2,b104),(r6,A2,b105),(r6,A2,b106),(r6,A2,b107),(r6,A2,b108),(r6,A2,b109),(r6,A2,b110),(r6,A2,b111),(r6,A2,b112),(r6,A2,b113),(r6,A2,b114),(r6,A2,b115),(r6,A2,b116),(r6,A2,b117),(r6,A2,b118),(r6,A2,b119),(r6,A2,b120),(r6,A2,b121),(r6,A2,b122),(r6,A2,b123),(r6,A2,b124),(r6,A2,b125),(r6,A2,b126),(r6,A2,b127),(r6,A2,b128),(r6,A2,b129),(r6,A2,b130),(r6,A2,b131),(r6,A2,b132),(r6,A2,b133),(r6,A2,b134),(r6,A3,b1),(r6,A3,b2),(r6,A3,b3),(r6,A3,b4),(r6,A3,b5),(r6,A3,b6),(r6,A3,b7),(r6,A3,b8),(r6,A3,b9),(r6,A3,b10),(r6,A3,b11),(r6,A3,b12),(r6,A3,b13),(r6,A3,b14),(r6,A3,b15),(r6,A3,b16),(r6,A3,b17),(r6,A3,b18),(r6,A3,b19),(r6,A3,b20),(r6,A3,b21),(r6,A3,b22),(r6,A3,b23),(r6,A3,b24),(r6,A3,b25),(r6,A3,b26),(r6,A3,b27),(r6,A3,b28),(r6,A3,b29),(r6,A3,b30),(r6,A3,b31),(r6,A3,b32),(r6,A3,b33),(r6,A3,b34),(r6,A3,b35),(r6,A3,b36),(r6,A3,b37),(r6,A3,b38),(r6,A3,b39),(r6,A3,b40),(r6,A3,b41),(r6,A3,b42),(r6,A3,b43),(r6,A3,b44),(r6,A3,b45),(r6,A3,b46),(r6,A3,b47),(r6,A3,b48),(r6,A3,b49),(r6,A3,b50),(r6,A3,b51),(r6,A3,b52),(r6,A3,b53),(r6,A3,b54),(r6,A3,b55),(r6,A3,b56),(r6,A3,b57),(r6,A3,b58),(r6,A3,b59),(r6,A3,b60),(r6,A3,b61),(r6,A3,b62),(r6,A3,b63),(r6,A3,b64),(r6,A3,b65),(r6,A3,b66),(r6,A3,b67),(r6,A3,b68),(r6,A3,b69),(r6,A3,b70),(r6,A3,b71),(r6,A3,b72),(r6,A3,b73),(r6,A3,b74),(r6,A3,b75),(r6,A3,b76),(r6,A3,b77),(r6,A3,b78),(r6,A3,b79),(r6,A3,b80),(r6,A3,b81),(r6,A3,b82),(r6,A3,b83),(r6,A3,b84),(r6,A3,b85),(r6,A3,b86),(r6,A3,b87),(r6,A3,b88),(r6,A3,b89),(r6,A3,b90),(r6,A3,b91),(r6,A3,b92),(r6,A3,b93),(r6,A3,b94),(r6,A3,b95),(r6,A3,b96),(r6,A3,b97),(r6,A3,b98),(r6,A3,b99),(r6,A3,b100),(r6,A3,b101),(r6,A3,b102),(r6,A3,b103),(r6,A3,b104),(r6,A3,b105),(r6,A3,b106),(r6,A3,b107),(r6,A3,b108),(r6,A3,b109),(r6,A3,b110),(r6,A3,b111),(r6,A3,b112),(r6,A3,b113),(r6,A3,b114),(r6,A3,b115),(r6,A3,b116),(r6,A3,b117),(r6,A3,b118),(r6,A3,b119),(r6,A3,b120),(r6,A3,b121),(r6,A3,b122),(r6,A3,b123),(r6,A3,b124),(r6,A3,b125),(r6,A3,b126),(r6,A3,b127),(r6,A3,b128),(r6,A3,b129),(r6,A3,b130),(r6,A3,b131),(r6,A3,b132),(r6,A3,b133),(r6,A3,b134),(r6,A4,b1),(r6,A4,b2),(r6,A4,b3),(r6,A4,b4),(r6,A4,b5),(r6,A4,b6),(r6,A4,b7),(r6,A4,b8),(r6,A4,b9),(r6,A4,b10),(r6,A4,b11),(r6,A4,b12),(r6,A4,b13),(r6,A4,b14),(r6,A4,b15),(r6,A4,b16),(r6,A4,b17),(r6,A4,b18),(r6,A4,b19),(r6,A4,b20),(r6,A4,b21),(r6,A4,b22),(r6,A4,b23),(r6,A4,b24),(r6,A4,b25),(r6,A4,b26),(r6,A4,b27),(r6,A4,b28),(r6,A4,b29),(r6,A4,b30),(r6,A4,b31),(r6,A4,b32),(r6,A4,b33),(r6,A4,b34),(r6,A4,b35),(r6,A4,b36),(r6,A4,b37),(r6,A4,b38),(r6,A4,b39),(r6,A4,b40),(r6,A4,b41),(r6,A4,b42),(r6,A4,b43),(r6,A4,b44),(r6,A4,b45),(r6,A4,b46),(r6,A4,b47),(r6,A4,b48),(r6,A4,b49),(r6,A4,b50),(r6,A4,b51),(r6,A4,b52),(r6,A4,b53),(r6,A4,b54),(r6,A4,b55),(r6,A4,b56),(r6,A4,b57),(r6,A4,b58),(r6,A4,b59),(r6,A4,b60),(r6,A4,b61),(r6,A4,b62),(r6,A4,b63),(r6,A4,b64),(r6,A4,b65),(r6,A4,b66),(r6,A4,b67),(r6,A4,b68),(r6,A4,b69),(r6,A4,b70),(r6,A4,b71),(r6,A4,b72),(r6,A4,b73),(r6,A4,b74),(r6,A4,b75),(r6,A4,b76),(r6,A4,b77),(r6,A4,b78),(r6,A4,b79),(r6,A4,b80),(r6,A4,b81),(r6,A4,b82),(r6,A4,b83),(r6,A4,b84),(r6,A4,b85),(r6,A4,b86),(r6,A4,b87),(r6,A4,b88),(r6,A4,b89),(r6,A4,b90),(r6,A4,b91),(r6,A4,b92),(r6,A4,b93),(r6,A4,b94),(r6,A4,b95),(r6,A4,b96),(r6,A4,b97),(r6,A4,b98),(r6,A4,b99),(r6,A4,b100),(r6,A4,b101),(r6,A4,b102),(r6,A4,b103),(r6,A4,b104),(r6,A4,b105),(r6,A4,b106),(r6,A4,b107),(r6,A4,b108),(r6,A4,b109),(r6,A4,b110),(r6,A4,b111),(r6,A4,b112),(r6,A4,b113),(r6,A4,b114),(r6,A4,b115),(r6,A4,b116),(r6,A4,b117),(r6,A4,b118),(r6,A4,b119),(r6,A4,b120),(r6,A4,b121),(r6,A4,b122),(r6,A4,b123),(r6,A4,b124),(r6,A4,b125),(r6,A4,b126),(r6,A4,b127),(r6,A4,b128),(r6,A4,b129),(r6,A4,b130),(r6,A4,b131),(r6,A4,b132),(r6,A4,b133),(r6,A4,b134),(r7,A1,b1),(r7,A1,b2),(r7,A1,b3),(r7,A1,b4),(r7,A1,b5),(r7,A1,b6),(r7,A1,b7),(r7,A1,b8),(r7,A1,b9),(r7,A1,b10),(r7,A1,b11),(r7,A1,b12),(r7,A1,b13),(r7,A1,b14),(r7,A1,b15),(r7,A1,b16),(r7,A1,b17),(r7,A1,b18),(r7,A1,b19),(r7,A1,b20),(r7,A1,b21),(r7,A1,b22),(r7,A1,b23),(r7,A1,b24),(r7,A1,b25),(r7,A1,b26),(r7,A1,b27),(r7,A1,b28),(r7,A1,b29),(r7,A1,b30),(r7,A1,b31),(r7,A1,b32),(r7,A1,b33),(r7,A1,b34),(r7,A1,b35),(r7,A1,b36),(r7,A1,b37),(r7,A1,b38),(r7,A1,b39),(r7,A1,b40),(r7,A1,b41),(r7,A1,b42),(r7,A1,b43),(r7,A1,b44),(r7,A1,b45),(r7,A1,b46),(r7,A1,b47),(r7,A1,b48),(r7,A1,b49),(r7,A1,b50),(r7,A1,b51),(r7,A1,b52),(r7,A1,b53),(r7,A1,b54),(r7,A1,b55),(r7,A1,b56),(r7,A1,b57),(r7,A1,b58),(r7,A1,b59),(r7,A1,b60),(r7,A1,b61),(r7,A1,b62),(r7,A1,b63),(r7,A1,b64),(r7,A1,b65),(r7,A1,b66),(r7,A1,b67),(r7,A1,b68),(r7,A1,b69),(r7,A1,b70),(r7,A1,b71),(r7,A1,b72),(r7,A1,b73),(r7,A1,b74),(r7,A1,b75),(r7,A1,b76),(r7,A1,b77),(r7,A1,b78),(r7,A1,b79),(r7,A1,b80),(r7,A1,b81),(r7,A1,b82),(r7,A1,b83),(r7,A1,b84),(r7,A1,b85),(r7,A1,b86),(r7,A1,b87),(r7,A1,b88),(r7,A1,b89),(r7,A1,b90),(r7,A1,b91),(r7,A1,b92),(r7,A1,b93),(r7,A1,b94),(r7,A1,b95),(r7,A1,b96),(r7,A1,b97),(r7,A1,b98),(r7,A1,b99),(r7,A1,b100),(r7,A1,b101),(r7,A1,b102),(r7,A1,b103),(r7,A1,b104),(r7,A1,b105),(r7,A1,b106),(r7,A1,b107),(r7,A1,b108),(r7,A1,b109),(r7,A1,b110),(r7,A1,b111),(r7,A1,b112),(r7,A1,b113),(r7,A1,b114),(r7,A1,b115),(r7,A1,b116),(r7,A1,b117),(r7,A1,b118),(r7,A1,b119),(r7,A1,b120),(r7,A1,b121),(r7,A1,b122),(r7,A1,b123),(r7,A1,b124),(r7,A1,b125),(r7,A1,b126),(r7,A1,b127),(r7,A1,b128),(r7,A1,b129),(r7,A1,b130),(r7,A1,b131),(r7,A1,b132),(r7,A1,b133),(r7,A1,b134),(r7,A2,b1),(r7,A2,b2),(r7,A2,b3),(r7,A2,b4),(r7,A2,b5),(r7,A2,b6),(r7,A2,b7),(r7,A2,b8),(r7,A2,b9),(r7,A2,b10),(r7,A2,b11),(r7,A2,b12),(r7,A2,b13),(r7,A2,b14),(r7,A2,b15),(r7,A2,b16),(r7,A2,b17),(r7,A2,b18),(r7,A2,b19),(r7,A2,b20),(r7,A2,b21),(r7,A2,b22),(r7,A2,b23),(r7,A2,b24),(r7,A2,b25),(r7,A2,b26),(r7,A2,b27),(r7,A2,b28),(r7,A2,b29),(r7,A2,b30),(r7,A2,b31),(r7,A2,b32),(r7,A2,b33),(r7,A2,b34),(r7,A2,b35),(r7,A2,b36),(r7,A2,b37),(r7,A2,b38),(r7,A2,b39),(r7,A2,b40),(r7,A2,b41),(r7,A2,b42),(r7,A2,b43),(r7,A2,b44),(r7,A2,b45),(r7,A2,b46),(r7,A2,b47),(r7,A2,b48),(r7,A2,b49),(r7,A2,b50),(r7,A2,b51),(r7,A2,b52),(r7,A2,b53),(r7,A2,b54),(r7,A2,b55),(r7,A2,b56),(r7,A2,b57),(r7,A2,b58),(r7,A2,b59),(r7,A2,b60),(r7,A2,b61),(r7,A2,b62),(r7,A2,b83),(r7,A2,b64),(r7,A2,b85),(r7,A2,b86),(r7,A2,b67),(r7,A2,b68),(r7,A2,b89),(r7,A2,b70),(r7,A2,b71),(r7,A2,b72),(r7,A2,b73),(r7,A2,b74),(r7,A2,b75),(r7,A2,b76),(r7,A2,b77),(r7,A2,b78),(r7,A2,b79),(r7,A2,b80),(r7,A2,b81),(r7,A2,b82),(r7,A2,b83),(r7,A2,b84),(r7,A2,b85),(r7,A2,b86),(r7,A2,b87),(r7,A2,b88),(r7,A2,b89),(r7,A2,b90),(r7,A2,b91),(r7,A2,b92),(r7,A2,b93),(r7,A2,b94),(r7,A2,b95),(r7,A2,b98),(r7,A2,b97),(r7,A2,b98),(r7,A2,b99),(r7,A2,b100),(r7,A2,b101),(r7,A2,b102),(r7,A2,b103),(r7,A2,b104),(r7,A2,b105),(r7,A2,b108),(r7,A2,b107),(r7,A2,b108),(r7,A2,b109),(r7,A2,b110),(r7,A2,b111),(r7,A2,b112),(r7,A2,b113),(r7,A2,b114),(r7,A2,b115),(r7,A2,b116),(r7,A2,b117),(r7,A2,b118),(r7,A2,b119),(r7,A2,b120),(r7,A2,b121),(r7,A2,b122),(r7,A2,b123),(r7,A2,b124),(r7,A2,b125),(r7,A2,b128),(r7,A2,b127),(r7,A2,b128),(r7,A2,b129),(r7,A2,b130),(r7,A2,b131),(r7,A2,b132),(r7,A2,b133),(r7,A2,b134),(r7,A3,b1),(r7,A3,b2),(r7,A3,b3),(r7,A3,b4),(r7,A3,b5),(r7,A3,b6),(r7,A3,b7),(r7,A3,b8),(r7,A3,b9),(r7,A3,b10),(r7,A3,b11),(r7,A3,b12),(r7,A3,b13),(r7,A3,b14),(r7,A3,b15),(r7,A3,b18),(r7,A3,b17),(r7,A3,b18),(r7,A3,b19),(r7,A3,b20),(r7,A3,b21),(r7,A3,b22),(r7,A3,b23),(r7,A3,b24),(r7,A3,b25),(r7,A3,b26),(r7,A3,b27),(r7,A3,b28),(r7,A3,b29),(r7,A3,b30),(r7,A3,b31),(r7,A3,b32),(r7,A3,b33),(r7,A3,b34),(r7,A3,b35),(r7,A3,b36),(r7,A3,b37),(r7,A3,b38),(r7,A3,b39),(r7,A3,b40),(r7,A3,b41),(r7,A3,b42),(r7,A3,b43),(r7,A3,b44),(r7,A3,b45),(r7,A3,b46),(r7,A3,b47),(r7,A3,b48),(r7,A3,b49),(r7,A3,b50),(r7,A3,b51),(r7,A3,b52),(r7,A3,b53),(r7,A3,b54),(r7,A3,b55),(r7,A3,b56),(r7,A3,b57),(r7,A3,b58),(r7,A3,b59),(r7,A3,b80),(r7,A3,b61),(r7,A3,b82),(r7,A3,b63),(r7,A3,b84),(r7,A3,b65),(r7,A3,b86),(r7,A3,b67),(r7,A3,b68),(r7,A3,b89),(r7,A3,b70),(r7,A3,b71),(r7,A3,b72),(r7,A3,b73),(r7,A3,b74),(r7,A3,b75),(r7,A3,b76),(r7,A3,b77),(r7,A3,b78),(r7,A3,b79),(r7,A3,b80),(r7,A3,b81),(r7,A3,b82),(r7,A3,b83),(r7,A3,b84),(r7,A3,b85),(r7,A3,b86),(r7,A3,b87),(r7,A3,b88),(r7,A3,b89),(r7,A3,b90),(r7,A3,b91),(r7,A3,b92),(r7,A3,b93),(r7,A3,b94),(r7,A3,b95),(r7,A3,b96),(r7,A3,b97),(r7,A3,b98),(r7,A3,b99),(r7,A3,b100),(r7,A3,b101),(r7,A3,b102),(r7,A3,b103),(r7,A3,b104),(r7,A3,b105),(r7,A3,b106),(r7,A3,b107),(r7,A3,b108),(r7,A3,b109),(r7,A3,b110),(r7,A3,b111),(r7,A3,b112),(r7,A3,b113),(r7,A3,b114),(r7,A3,b115),(r7,A3,b116),(r7,A3,b117),(r7,A3,b118),(r7,A3,b119),(r7,A3,b120),(r7,A3,b121),(r7,A3,b122),(r7,A3,b123),(r7,A3,b124),(r7,A3,b125),(r7,A3,b126),(r7,A3,b127),(r7,A3,b128),(r7,A3,b129),(r7,A3,b130),(r7,A3,b131),(r7,A3,b132),(r7,A3,b133),(r7,A3,b134),(r7,A4,b1),(r7,A4,b2),(r7,A4,b3),(r7,A4,b4),(r7,A4,b5),(r7,A4,b6),(r7,A4,b7),(r7,A4,b8),(r7,A4,b9),(r7,A4,b10),(r7,A4,b11),(r7,A4,b12),(r7,A4,b13),(r7,A4,b14),(r7,A4,b15),(r7,A4,b16),(r7,A4,b17),(r7,A4,b18),(r7,A4,b19),(r7,A4,b20),(r7,A4,b21),(r7,A4,b22),(r7,A4,b23),(r7,A4,b24),(r7,A4,b25),(r7,A4,b28),(r7,A4,b27),(r7,A4,b28),(r7,A4,b29),(r7,A4,b30),(r7,A4,b31),(r7,A4,b32),(r7,A4,b33),(r7,A4,b34),(r7,A4,b35),(r7,A4,b36),(r7,A4,b37),(r7,A4,b38),(r7,A4,b39),(r7,A4,b40),(r7,A4,b41),(r7,A4,b42),(r7,A4,b43),(r7,A4,b44),(r7,A4,b45),(r7,A4,b48),(r7,A4,b47),(r7,A4,b48),(r7,A4,b49),(r7,A4,b50),(r7,A4,b51),(r7,A4,b52),(r7,A4,b53),(r7,A4,b54),(r7,A4,b55),(r7,A4,b56),(r7,A4,b57),(r7,A4,b58),(r7,A4,b59),(r7,A4,b60),(r7,A4,b61),(r7,A4,b62),(r7,A4,b63),(r7,A4,b64),(r7,A4,b65),(r7,A4,b66),(r7,A4,b67),(r7,A4,b68),(r7,A4,b69),(r7,A4,b70),(r7,A4,b71),(r7,A4,b72),(r7,A4,b73),(r7,A4,b74),(r7,A4,b75),(r7,A4,b76),(r7,A4,b77),(r7,A4,b78),(r7,A4,b79),(r7,A4,b80),(r7,A4,b81),(r7,A4,b82),(r7,A4,b83),(r7,A4,b84),(r7,A4,b85),(r7,A4,b86),(r7,A4,b87),(r7,A4,b88),(r7,A4,b89),(r7,A4,b90),(r7,A4,b91),(r7,A4,b92),(r7,A4,b93),(r7,A4,b94),(r7,A4,b95),(r7,A4,b96),(r7,A4,b97),(r7,A4,b98),(r7,A4,b99),(r7,A4,b100),(r7,A4,b101),(r7,A4,b102),(r7,A4,b103),(r7,A4,b104),(r7,A4,b105),(r7,A4,b106),(r7,A4,b107),(r7,A4,b108),(r7,A4,b109),(r7,A4,b110),(r7,A4,b111),(r7,A4,b112),(r7,A4,b113),(r7,A4,b114),(r7,A4,b115),(r7,A4,b116),(r7,A4,b117),(r7,A4,b118),(r7,A4,b119),(r7,A4,b120),(r7,A4,b121),(r7,A4,b122),(r7,A4,b123),(r7,A4,b124),(r7,A4,b125),(r7,A4,b126),(r7,A4,b127),(r7,A4,b128),(r7,A4,b129),(r7,A4,b130),(r7,A4,b131),(r7,A4,b132),(r7,A4,b133),(r7,A4,b134),(r8,A1,b1),(r8,A1,b2),(r8,A1,b3),(r8,A1,b4),(r8,A1,b5),(r8,A1,b6),(r8,A1,b7),(r8,A1,b8),(r8,A1,b9),(r8,A1,b10),(r8,A1,b11),(r8,A1,b12),(r8,A1,b13),(r8,A1,b14),(r8,A1,b15),(r8,A1,b16),(r8,A1,b17),(r8,A1,b18),(r8,A1,b19),(r8,A1,b20),(r8,A1,b21),(r8,A1,b22),(r8,A1,b23),(r8,A1,b24),(r8,A1,b25),(r8,A1,b26),(r8,A1,b27),(r8,A1,b28),(r8,A1,b29),(r8,A1,b30),(r8,A1,b31),(r8,A1,b32),(r8,A1,b33),(r8,A1,b34),(r8,A1,b35),(r8,A1,b36),(r8,A1,b37),(r8,A1,b38),(r8,A1,b39),(r8,A1,b40),(r8,A1,b41),(r8,A1,b42),(r8,A1,b43),(r8,A1,b44),(r8,A1,b45),(r8,A1,b46),(r8,A1,b47),(r8,A1,b48),(r8,A1,b49),(r8,A1,b50),(r8,A1,b51),(r8,A1,b52),(r8,A1,b53),(r8,A1,b54),(r8,A1,b55),(r8,A1,b56),(r8,A1,b57),(r8,A1,b58),(r8,A1,b59),(r8,A1,b60),(r8,A1,b61),(r8,A1,b62),(r8,A1,b63),(r8,A1,b64),(r8,A1,b65),(r8,A1,b66),(r8,A1,b67),(r8,A1,b68),(r8,A1,b69),(r8,A1,b70),(r8,A1,b71),(r8,A1,b72),(r8,A1,b73),(r8,A1,b74),(r8,A1,b75),(r8,A1,b76),(r8,A1,b77),(r8,A1,b78),(r8,A1,b79),(r8,A1,b80),(r8,A1,b81),(r8,A1,b82),(r8,A1,b83),(r8,A1,b84),(r8,A1,b85),(r8,A1,b86),(r8,A1,b87),(r8,A1,b88),(r8,A1,b89),(r8,A1,b90),(r8,A1,b91),(r8,A1,b92),(r8,A1,b93),(r8,A1,b94),(r8,A1,b95),(r8,A1,b96),(r8,A1,b97),(r8,A1,b98),(r8,A1,b99),(r8,A1,b100),(r8,A1,b101),(r8,A1,b102),(r8,A1,b103),(r8,A1,b104),(r8,A1,b105),(r8,A1,b106),(r8,A1,b107),(r8,A1,b108),(r8,A1,b109),(r8,A1,b110),(r8,A1,b111),(r8,A1,b112),(r8,A1,b113),(r8,A1,b114),(r8,A1,b115),(r8,A1,b116),(r8,A1,b117),(r8,A1,b118),(r8,A1,b119),(r8,A1,b120),(r8,A1,b121),(r8,A1,b122),(r8,A1,b123),(r8,A1,b124),(r8,A1,b125),(r8,A1,b126),(r8,A1,b127),(r8,A1,b128),(r8,A1,b129),(r8,A1,b130),(r8,A1,b131),(r8,A1,b132),(r8,A1,b133),(r8,A1,b134),(r8,A2,b1),(r8,A2,b2),(r8,A2,b3),(r8,A2,b4),(r8,A2,b5),(r8,A2,b6),(r8,A2,b7),(r8,A2,b8),(r8,A2,b9),(r8,A2,b10),(r8,A2,b11),(r8,A2,b12),(r8,A2,b13),(r8,A2,b14),(r8,A2,b15),(r8,A2,b16),(r8,A2,b17),(r8,A2,b18),(r8,A2,b19),(r8,A2,b20),(r8,A2,b21),(r8,A2,b22),(r8,A2,b23),(r8,A2,b24),(r8,A2,b25),(r8,A2,b26),(r8,A2,b27),(r8,A2,b28),(r8,A2,b29),(r8,A2,b30),(r8,A2,b31),(r8,A2,b32),(r8,A2,b33),(r8,A2,b34),(r8,A2,b35),(r8,A2,b36),(r8,A2,b37),(r8,A2,b38),(r8,A2,b39),(r8,A2,b40),(r8,A2,b41),(r8,A2,b42),(r8,A2,b43),(r8,A2,b44),(r8,A2,b45),(r8,A2,b46),(r8,A2,b47),(r8,A2,b48),(r8,A2,b49),(r8,A2,b50),(r8,A2,b51),(r8,A2,b52),(r8,A2,b53),(r8,A2,b54),(r8,A2,b55),(r8,A2,b56),(r8,A2,b57),(r8,A2,b58),(r8,A2,b59),(r8,A2,b60),(r8,A2,b61),(r8,A2,b62),(r8,A2,b63),(r8,A2,b64),(r8,A2,b65),(r8,A2,b66),(r8,A2,b67),(r8,A2,b68),(r8,A2,b69),(r8,A2,b70),(r8,A2,b71),(r8,A2,b72),(r8,A2,b73),(r8,A2,b74),(r8,A2,b75),(r8,A2,b76),(r8,A2,b77),(r8,A2,b78),(r8,A2,b79),(r8,A2,b80),(r8,A2,b81),(r8,A2,b82),(r8,A2,b83),(r8,A2,b84),(r8,A2,b85),(r8,A2,b86),(r8,A2,b87),(r8,A2,b88),(r8,A2,b89),(r8,A2,b90),(r8,A2,b91),(r8,A2,b92),(r8,A2,b93),(r8,A2,b94),(r8,A2,b95),(r8,A2,b96),(r8,A2,b97),(r8,A2,b98),(r8,A2,b99),(r8,A2,b100),(r8,A2,b101),(r8,A2,b102),(r8,A2,b103),(r8,A2,b104),(r8,A2,b105),(r8,A2,b106),(r8,A2,b107),(r8,A2,b108),(r8,A2,b109),(r8,A2,b110),(r8,A2,b111),(r8,A2,b112),(r8,A2,b113),(r8,A2,b114),(r8,A2,b115),(r8,A2,b116),(r8,A2,b117),(r8,A2,b118),(r8,A2,b119),(r8,A2,b120),(r8,A2,b121),(r8,A2,b122),(r8,A2,b123),(r8,A2,b124),(r8,A2,b125),(r8,A2,b126),(r8,A2,b127),(r8,A2,b128),(r8,A2,b129),(r8,A2,b130),(r8,A2,b131),(r8,A2,b132),(r8,A2,b133),(r8,A2,b134),(r8,A3,b1),(r8,A3,b2),(r8,A3,b3),(r8,A3,b4),(r8,A3,b5),(r8,A3,b6),(r8,A3,b7),(r8,A3,b8),(r8,A3,b9),(r8,A3,b10),(r8,A3,b11),(r8,A3,b12),(r8,A3,b13),(r8,A3,b14),(r8,A3,b15),(r8,A3,b16),(r8,A3,b17),(r8,A3,b18),(r8,A3,b19),(r8,A3,b20),(r8,A3,b21),(r8,A3,b22),(r8,A3,b23),(r8,A3,b24),(r8,A3,b25),(r8,A3,b26),(r8,A3,b27),(r8,A3,b28),(r8,A3,b29),(r8,A3,b30),(r8,A3,b31),(r8,A3,b32),(r8,A3,b33),(r8,A3,b34),(r8,A3,b35),(r8,A3,b36),(r8,A3,b37),(r8,A3,b38),(r8,A3,b39),(r8,A3,b40),(r8,A3,b41),(r8,A3,b42),(r8,A3,b43),(r8,A3,b44),(r8,A3,b45),(r8,A3,b46),(r8,A3,b47),(r8,A3,b48),(r8,A3,b49),(r8,A3,b50),(r8,A3,b51),(r8,A3,b52),(r8,A3,b53),(r8,A3,b54),(r8,A3,b55),(r8,A3,b56),(r8,A3,b57),(r8,A3,b58),(r8,A3,b59),(r8,A3,b60),(r8,A3,b61),(r8,A3,b62),(r8,A3,b63),(r8,A3,b64),(r8,A3,b65),(r8,A3,b66),(r8,A3,b67),(r8,A3,b68),(r8,A3,b69),(r8,A3,b70),(r8,A3,b71),(r8,A3,b72),(r8,A3,b73),(r8,A3,b74),(r8,A3,b75),(r8,A3,b76),(r8,A3,b77),(r8,A3,b78),(r8,A3,b79),(r8,A3,b80),(r8,A3,b81),(r8,A3,b82),(r8,A3,b83),(r8,A3,b84),(r8,A3,b85),(r8,A3,b86),(r8,A3,b87),(r8,A3,b88),(r8,A3,b89),(r8,A3,b90),(r8,A3,b91),(r8,A3,b92),(r8,A3,b93),(r8,A3,b94),(r8,A3,b95),(r8,A3,b96),(r8,A3,b97),(r8,A3,b98),(r8,A3,b99),(r8,A3,b100),(r8,A3,b101),(r8,A3,b102),(r8,A3,b103),(r8,A3,b104),(r8,A3,b105),(r8,A3,b106),(r8,A3,b107),(r8,A3,b108),(r8,A3,b109),(r8,A3,b110),(r8,A3,b111),(r8,A3,b112),(r8,A3,b113),(r8,A3,b114),(r8,A3,b115),(r8,A3,b116),(r8,A3,b117),(r8,A3,b118),(r8,A3,b119),(r8,A3,b120),(r8,A3,b121),(r8,A3,b122),(r8,A3,b123),(r8,A3,b124),(r8,A3,b125),(r8,A3,b126),(r8,A3,b127),(r8,A3,b128),(r8,A3,b129),(r8,A3,b130),(r8,A3,b131),(r8,A3,b132),(r8,A3,b133),(r8,A3,b134),(r8,A4,b1),(r8,A4,b2),(r8,A4,b3),(r8,A4,b4),(r8,A4,b5),(r8,A4,b6),(r8,A4,b7),(r8,A4,b8),(r8,A4,b9),(r8,A4,b10),(r8,A4,b11),(r8,A4,b12),(r8,A4,b13),(r8,A4,b14),(r8,A4,b15),(r8,A4,b16),(r8,A4,b17),(r8,A4,b18),(r8,A4,b19),(r8,A4,b20),(r8,A4,b21),(r8,A4,b22),(r8,A4,b23),(r8,A4,b24),(r8,A4,b25),(r8,A4,b26),(r8,A4,b27),(r8,A4,b28),(r8,A4,b29),(r8,A4,b30),(r8,A4,b31),(r8,A4,b32),(r8,A4,b33),(r8,A4,b34),(r8,A4,b35),(r8,A4,b36),(r8,A4,b37),(r8,A4,b38),(r8,A4,b39),(r8,A4,b40),(r8,A4,b41),(r8,A4,b42),(r8,A4,b43),(r8,A4,b44),(r8,A4,b45),(r8,A4,b46),(r8,A4,b47),(r8,A4,b48),(r8,A4,b49),(r8,A4,b50),(r8,A4,b51),(r8,A4,b52),(r8,A4,b53),(r8,A4,b54),(r8,A4,b55),(r8,A4,b56),(r8,A4,b57),(r8,A4,b58),(r8,A4,b59),(r8,A4,b60),(r8,A4,b61),(r8,A4,b62),(r8,A4,b63),(r8,A4,b64),(r8,A4,b65),(r8,A4,b66),(r8,A4,b67)(r8,A4,b68),(r8,A4,b69),(r8,A4,b70),(r8,A4,b71),(r8,A4,b72),(r8,A4,b73),(r8,A4,b74),(r8,A4,b75),(r8,A4,b76),(r8,A4,b77),(r8,A4,b78),(r8,A4,b79),(r8,A4,b80),(r8,A4,b81),(r8,A4,b82),(r8,A4,b83),(r8,A4,b84),(r8,A4,b85),(r8,A4,b86),(r8,A4,b87),(r8,A4,b88),(r8,A4,b89),(r8,A4,b90),(r8,A4,b91),(r8,A4,b92),(r8,A4,b93),(r8,A4,b94),(r8,A4,b95),(r8,A4,b96),(r8,A4,b97),(r8,A4,b98),(r8,A4,b99),(r8,A4,b100),(r8,A4,b101),(r8,A4,b102),(r8,A4,b103),(r8,A4,b104),(r8,A4,b105),(r8,A4,b106),(r8,A4,b107),(r8,A4,b108),(r8,A4,b109),(r8,A4,b110),(r8,A4,b111),(r8,A4,b112),(r8,A4,b113),(r8,A4,b114),(r8,A4,b115),(r8,A4,b116),(r8,A4,b117),(r8,A4,b118),(r8,A4,b119),(r8,A4,b120),(r8,A4,b121),(r8,A4,b122),(r8,A4,b123),(r8,A4,b124),(r8,A4,b125),(r8,A4,b126),(r8,A4,b127),(r8,A4,b128),(r8,A4,b129),(r8,A4,b130),(r8,A4,b131),(r8,A4,b132),(r8,A4,b133)or (r8,A4,b134).

The present compounds are useful in disease induced by the production,secretion or deposition of amyloid β protein, and are effective intreatment and/or prevention, and symptom improvement of such as dementiaof the Alzheimer's type (Alzheimer's disease, senile dementia ofAlzheimer type), Down's syndrome, memory impairment, prion disease(Creutzfeldt-Jakob disease), mild cognitive impairment (MCI), Dutch typeof hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, other type of degenerative dementia, mixed dementia withAlzheimer's and vascular type, dementia with Parkinson's Disease,dementia with progressive supranuclear palsy, dementia withCortico-basal degeneration, Alzheimer's disease with diffuse Lewy bodydisease, age-related macular degeneration, Parkinson's Disease, amyloidangiopathy and so on.

In the present invention, “treating Alzheimer's disease” includesprevention of aggravation of MCI and prevention of onset of familialAlzheimer's disease. In the present invention, “a pharmaceuticalcomposition for treating Alzheimer's disease” includes a pharmaceuticalcomposition for prevention of aggravation of MCI and prevention of onsetof familial Alzheimer's disease.

Since the present compound has high inhibitory activity on BACE1, and/orhas high selectivity on other enzymes, it can be a medicament withreduced side effect. Further, since the compound has high effect ofreducing amyloid β production in a cell system, particularly, has higheffect of reducing amyloid β production in brain, it can be an excellentmedicament. In addition, by converting the compound into an opticallyactive compound having suitable stereochemistry, the compound can be amedicament having a larger safety margin on the side effect. Inaddition, the present compound also has advantages that metabolismstability is high, solubility is high, oral absorbability is high, goodbioavailability is exhibited, clearance is good, brain transference ishigh, a half life is high, non-protein binding rate is high, hERGchannel inhibition is low, CYP inhibition is low, CYP MBI (irreversibleinhibition (mechanism-based inhibition)) is low and/or an Ames test isnegative.

The present compounds can be administrated in combination with otherpharmaceutical agents such as other therapeutic drugs for Alzheimer'sdisease, e.g., acetylcholinesterase and the like. The present compoundscan be treated with concomitantly with the anti-dementia agents such asDonepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil,Memantine, and Vinpocetine.

When the present compound is administered to a human, it can beadministered orally as powders, granules, tablets, capsules, pills,solutions, or the like, or parenterally as injectables, suppositories,transdermal absorbable agents, inhalations, or the like. In addition,the present compound can be formulated into pharmaceutical preparationsby adding pharmaceutical additives such as excipients, binders, wettingagents, disintegrating agents, lubricants and the like, which aresuitable for formulations and an effective amount of the presentcompound.

A dose is different depending on state of disease, an administrationroute, and an age and a weight of a patient, and is usually 0.1 μg to 1g/day, preferably 0.01 to 200 mg/day when orally administered to anadult, and is usually 1 μg to 10 g/day, preferably 0.1 to 2 g/day whenparenterally administered.

EXAMPLE

Following examples and test examples illustrate the present invention inmore detail, but the present invention is not limited by these examples.

¹H-NMR was measured in deuterium chloroform (CDCl₃) usingtetramethylsilane as an internal standard, or measured indimethylsulfoxide-D6 (DMSO-d₆). δ values were shown as ppm. Bindingconstants (J) were shown as Hz. In the data, s, d, t, m, br or brs meanssinglet, doublet, triplet, multiplet, broad or broad singlet,respectively.

In examples, the meaning of each abbreviation is as follows:

Me methyl

Bu butyl

Bz benzoyl

Boc tert-butoxycarbonyl

THF tetrahydrofuran

DMF N,N-dimethylformamide

EDC 1-ethyl-3-(3-dimethylamino propyl)carbodiimide

DIBAL diisobutylaluminum hydride

MCPBA meta-chloroperbenzoic acid

LC/MS data of Compounds (I-1) to (I-54) were measured under thecondition A, Compound (I-55) to (I-67) were measured under the conditionB, and a retention time and [M+H]⁺ are shown.

Condition A

Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

Flow rate: 1.6 mL/min

Column oven: 50° C.

UV detection wavelength: 254 nm

Mobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing acetonitrile solution

Gradient: performing linear gradient of 10% to 100% solvent [B] for 3minutes, and keeping 100% solvent [B] for 1 minute

Condition B

Column: XBridge (Registered trademark) C18 (5 μm, i.d. 4.6×50 mm)(Waters)

Flow rate: 3 mL/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B]is 0.1% formic acid-containing acetonitrile solution

Gradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes wasperformed, and 100% solvent [B] was maintained for 1 minutes.

Example 1 Synthesis of Compound (I-12) and (I-13)

Step 1

To a solution of Compound 1 (1.20 g) in acetone (70 ml)-water (40 ml)was added a solution of benzoyl isothiocyanate (0.82 g) in acetone at 0°C. and the mixture was stirred for 2 hours at room temperature. Thesolvent was evaporated under reduced pressure, the residue was purifiedby column chromatography to give Compound 2 (1.35 g).

¹H-NMR (CDCl₃) δ: 1.69 (1H, t, J=4.7 Hz), 2.14 (3H, s) 2.21-2.31 (1H,m), 2.73-2.83 (1H, m), 3.78-3.98 (2H, m), 7.15 (1H, dd, J=11.1, 9.1 Hz)7.48-7.55 (2H, m), 7.60-7.67 (1H, m), 7.85 (2H, d, 7.2 Hz), 8.14-8.20(1H, m), 8.30-8.34 (1H, m), 8.81 (1H, s), 11.56 (1H, s).

Step 2

To a solution of Compound 2 (1.26 g) obtained in Step 1 in acetonitrile(5 ml) were added methyl iodide (0.30 ml) and diisopropylethylamine(0.84 ml). The mixture was stirred at room temperature for 2 hours andat 40° C. for 2 hours. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by column chromatography to give Compound 3 (1.11g).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.30-2.40 (1H, m), 2.66-2.74 (1H, m),4.01-4.10 (1H, m), 4.42-4.49 (1H, m), 7.25-7.32 (1H, m), 8.37 (1H, dd,J=7.1, 2.9 Hz) 7.39-7.54 (3H, m), 8.21-8.29 (3H, m), 11.90 (1H, br).

Step 3

To Compound 3 (1.10 g) obtained in Step 2 was added concentratedsulfuric acid (3.28 ml) and the mixture was stirred at 80° C. for 1.5hours. The reaction mixture was added to a saturated aqueous sodiumbicarbonate solution and the mixture was extracted with ethyl acetate.The organic layer was successively washed with water and brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by column chromatographyto give Compound (I-12) (0.615 g).

¹H-NMR (CDCl₃) δ: 1.58 (3H, s), 2.22 (2H, t, J=5.4 Hz), 3.86-3.94 (1H,m), 4.15-4.25 (3H, m), 7.14 (1H, dd, J=10.7, 8.9 Hz), 8.09-8.15 (1H, m),8.62 (1H, dd, J=7.0, 3.0 Hz).

Step 4

To a solution of Compound (I-12) (614 mg) obtained in Step 3 in THF (5ml) was added 10% palladium-carbon (120 mg) and the mixture was stirredfor 20 hours under hydrogen atmosphere. The reaction solution wasfiltered through Celite and the filtrate was concentrated under reducedpressure. The obtained residue was purified by column chromatography andrecrystallized from ethyl acetate-hexane to give Compound (I-13) (400mg).

¹H-NMR (CDCl₃) δ: 1.54 (3H, s), 1.97-2.07 (1H, m), 2.30-2.38 (1H, m),3.54 (2H, brs), 3.83 (1H, dt, J=3.2, 10.6 Hz), 4.10 (1H, ddd, 10.6, 4.7,4.2 Hz), 6.48 (1H, ddd, 8.4, 3.7, 3.2 Hz), 6.78 (1H, dd, J=11.8, 8.4Hz), 6.86 (1H, dd, J=6.9, 3.0 Hz).

Example 2 Synthesis of Compounds (I-14) and (I-15)

Step 1

To a solution of Compound 4 (1.1 g) obtained by Reference Examplementioned below in tetrahydrofuran (10 ml) was added benzoyl isocyanate(854 μl) at 0° C. and the mixture was stirred at room temperature for 30minutes. To the mixture was added N-bromosuccinimide (675 mg) and themixture was stirred at room temperature for 30 minutes. To the mixturewas added ethyl acetate and the mixture was successively washed withwater and brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give Compound (5) (2.4 g) as acrude product.

Step 2

To a solution of Compound (5) (2.4 g) obtained in Step 1 intetrahydrofuran (12 ml) and dimethylsulfide (12 ml) was added sodiumtert-butoxide and the mixture was stirred at room temperature for 2hours. The reaction solution was poured into 1 mol/L hydrochloric acidand extracted with ethyl acetate. The organic layer was washedsuccessively with 1 mol/L aqueous hydrochloric acid solution, water andbrine and dried over magnesium sulfate. The solvent was evaporated underreduced pressure to give Compound (6) (2.1 g) as a crude product.

Step 3

To a solution of Compound (6) (2.1 g) obtained in Step 2 intetrahydrofuran (16 ml) were added di-tert-butyl dicarbonate (1.8 ml)and N,N-dimethyl-4-aminopyridine (9.2 mg). The mixture was stirred atroom temperature for 30 minutes. To the mixture was added triethylamine(522 μl), and the mixture was stirred for 30 minutes. To the mixturewere added N,N-dimethyl-4-aminopyridine (460 mg) and di-tert-butyldicarbonate (0.9 ml), and the mixture was stirred at room temperaturefor 20 minutes. To the mixture was added 2 mol/L aqueous solution ofpotassium carbonate and the mixture was extracted with ethyl acetate.The organic layer was washed with 1 mol/L aqueous solution of citricacid and brine and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was subjectto column chromatography to give Compound (7) (0.99 g).

¹H-NMR (CDCl₃) δ: 1.40 (3H, s), 1.47 (9H, s), 1.53 (9H, s), 2.51 (1H, d,J=14.0 Hz), 2.88 (1H, d, J=14.0 Hz), 4.38 (1H, s), 4.75 (1H, s), 6.30(1H, s), 6.87 (1H, br), 6.93 (1H, dd, J=11.7, 9.0 Hz), 7.42-7.65 (4H,m), 7.80-7.83 (2H, m).

Step 4

To a solution of Compound (7) (914 mg) obtained in Step 3 in methanol (3ml) and tetrahydrofuran (5 ml) was added 1 mol/L aqueous solution ofsodium hydroxide (1.7 ml) at 0° C. and the mixture was stirred for 80minutes. The reaction mixture was extracted with ethyl acetate, washedwith brine and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was subjected to columnchromatography to give Compound (I-14) (695 mg).

¹H-NMR (CDCl₃) δ: 1.52 (9H, s) and 1.54 (9H, s) 1.75 (3H, s) 2.70 (1H,d, J=14.0 Hz), 3.20 (1H, d, J=14.0 Hz) 4.25 (1H, s), 4.66 (1H, s), 6.48(1H, s), 6.96 (1H, br), 7.02 (1H, dd, J=11.4, 9.0 Hz), 7.51 (1H, m),10.0 (1H, s).

Step 5

To a solution of Compound (I-14) obtained in Step 4 in methylenechloride (2 ml) was added trifluoroacetate (2 ml) at 0° C. and themixture was stirred at room temperature for 80 minutes. The solvent wasevaporated under reduced pressure and were added ethyl acetate and asaturated aqueous sodium bicarbonate solution. The mixture was stirredvigorously. The mixture was extracted with ethyl acetate, washed withbrine and dried over magnesium sulfate. The solvent was evaporated underreduces pressure to give Compound (I-15) (427 mg) as a crude product.

¹H-NMR (CDCl₃) δ: 1.63 (3H, s), 2.69 (1H, d, J=14.1 Hz), 3.02 (1H, d,J=14.1 Hz), 3.58 (2H, s), 4.28 (1H, s), 4.60 (1H, s), 6.51 (1H, ddd,J=8.8, 3.2, 2.8 Hz), 6.72 (1H, dd, J=6.9, 2.8 Hz), 6.81 (1H, dd, J=11.7,8.8 Hz).

Reference Example

Step 1

Compound (9) (12 g) was dissolved in tetrahydrofuran (240 ml). To thesolution was dropwisely added 1 mol/L allylmagnesium bromide/ethersolution during 1 hour at −78° C. The mixture was stirred at −78° C. for1 hour and poured into a saturated aqueous solution of ammoniumchloride. The mixture was extracted with ethyl acetate and the organiclayer was dried over anhydrous sodium sulfate. After removing aninorganic material by filtration, the solvent was evaporated underreduced pressure. The residue was subjected to column chromatography togive Compound (10) (9.7 g).

¹H-NMR (CDCl₃) δ: 1.21 (9H, s), 1.68 (3H, s), 2.79 (1H, dd, J=13.4, 7.3Hz), 2.92 (1H, dd, J=13.4, 6.8 Hz), 4.16 (1H, s), 5.10 (1H, d, J=9.6Hz), 5.13 (1H, d, J=17.2 Hz) 5.52-5.66 (1H, m), 6.95 (1H, dd, J=10.6,10.1 Hz), 7.55-7.62 (1H, m), 7.67-7.72 (1H, m), 9.96 (1H, s).

Step 2

Compound (10) (3.99 g) was dissolved in ethanol (20 ml). To the solutionwas added a solution of 1 mol/L hydrochloric acid-ethanol with stirringat room temperature and the mixture was stirred for 1 hour at roomtemperature. The solvent was evaporated under reduced pressure. Theresidue was diluted with ethyl acetate and the solution was extractedwith 2 mol/L hydrochloric acid. The obtained aqueous layer was madealkalinized with potassium carbonate (pH 8 to 9), and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. After removing an inorganic material by filtration, the solventwas evaporated under reduced pressure to give Compound (4).

¹H-NMR (CDCl₃) δ: 1.51 (3H, s), 1.75-1.89 (2H, br), 2.47 (1H, dd,J=13.1, 8.1 Hz) 2.76 (1H, dd, J=13.1, 7.1 Hz), 5.03-5.11 (2H, m),5.46-5.58 (1H, m), 7.01-7.08 (1H, m), 7.52-7.60 (2H, m), 8.25-8.36 (1H,br).

Example 3 Synthesis of Compound (I-54)

Step 1

Compound (9) prepared by the method described in WO2009/151098 (3.00 g)was dissolved in tetrahydrofuran (30 ml) and cooled in a dry ice-acetonebath under the nitrogen atmosphere. To the solution was dropwisely added2-methyl allyl magnesium chloride (0.5 mol/L solution in THF, 85.0 ml)at −78° C. and stirred at −78° C. for 2 hours. To the reaction mixturewere added a saturated aqueous solution of ammonium chloride and water.The mixture was extracted with ethyl acetate and washed with water andbrine successively. The organic layer was dried over anhydrous magnesiumchloride and the solvent was evaporated under reduced pressure. Theobtained residue was purified by column chromatography to give Compound(11) (2.49 g).

¹H-NMR (CDCl₃) δ: 1.26 (s, 9H), 1.38 (s, 3H), 1.86 (s, 3H), 2.84 (ABq,J=13.4 Hz, 2H), 4.21 (s, 1H), 4.81 (s, 1H), 4.92 (d, J=1.5 Hz, 1H), 7.05(dd, J=11.7, 8.7 Hz, 1H), 7.45-7.51 (m, 1H), 7.74 (dd, J=6.8, 2.7 Hz,1H), 8.37 (brs, 1H).

Step 2

A solution of Compound (11) (4.17 g) in methylene chloride (60 ml) wascooled in a dry ice-acetone bath and ozone gas was bubbled through thesolution at −78° C. When the color of the reaction solution changed toblue, babbling was stopped then babbling nitrogen gas. Triethylamine(4.25 ml) was added to the reaction solution and stirred for 1 hour at−78° C. Water was added to the mixture and extracted with ethyl acetate.The organic layer was washed with brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive Compound (12) (4.43 g).

¹H-NMR (CDCl₃) δ: 1.31 (s, 9H), 1.73 (s, 3H), 2.10 (s, 3H), 3.35 (dd,J=18.6, 2.5 Hz, 1H), 3.66 (d, J=18.6 Hz, 1H), 5.35 (s, 1H), 6.99 (dd,J=11.9, 8.7 Hz, 1H), 7.30-7.35 (m, 1H), 7.98 (dd, J=7.2, 2.7 Hz, 1H).

Step 3

To a solution of Compound (12) (4.19 g) in methanol (30 ml) was added 4mol/L hydrochloric acid-1,4-dioxane solution (3.57 ml) then the mixturewas stirred at room temperature for 2 hours. The solvent was evaporatedunder reduced pressure. To the obtained residue was added water and themixture was extracted with ethyl acetate. The organic layer was washedwith water. The combined aqueous layer was made alkalinized with asaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The organic layer was successively washed with water and brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure to give Compound (13) (3.00 g).

¹H-NMR (CDCl₃) δ: 1.48 (s, 3H), 2.06 (s, 3H), 2.18 (br, 2H), 2.86 (d,J=17.8 Hz, 1H), 3.44 (d, J=17.8 Hz, 1H), 7.01 (dd, J=11.7, 8.7 Hz, 1H),7.60-7.70 (m, 2H), 8.17 (br, 1H).

Step 4

To a solution of Compound (13) (2.48 g) in ethyl acetate (25 ml)-toluene(15 ml) were added potassium carbonate (2.24 g) and water (20 ml) thenthe mixture was cooled in an ice bath. To the mixture was added asolution of thiophosgene (1.40 g) in toluene (10 ml) and stirred for 1hour at 0° C. Water was added to the reaction solution and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and brine, successively. The organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure to give Compound (14) (2.82 g).

¹H-NMR (CDCl₃) δ: 1.90 (s, 3H), 2.15 (s, 3H), 3.34 (ABq, J=17.1 Hz, 2H),7.07 (dd, J=11.4, 8.9 Hz, 1H), 7.57 (dd, J=6.9, 2.9 Hz, 1H), 7.79-7.85(m, 1H), 8.13 (br, 1H).

Step 5

To a solution of Compound (14) (2.82 g) in THF (40 ml) was addedbis(2,4-dimethoxybenzyl)amine (3.08 g) then the mixture was stirred for16 hours at room temperature. The solvent was evaporated under reducedpressure. Water and 2 mol/L hydrochloric acid were added to the residueand was extracted with ethyl acetate. The organic layer was washed withwater, a saturated aqueous sodium bicarbonate solution, water and brine,successively and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was purifiedby column chromatography to give Compound (15) (4.61 g).

¹H-NMR (CDCl₃) δ: 1.81 (s, 3H), 2.15 (s, 3H), 3.11 (d, J=16.8 Hz, 1H),3.79 (s, 6H), 3.80 (s, 6H), 4.46 (d, J=16.8 Hz, 1H), 4.77 (br, 2H), 5.03(br, 2H), 6.45-6.52 (m, 4H), 6.86 (brs, 1H), 7.00 (dd, J=11.3, 8.7 Hz,1H), 7.11-7.20 (m, 3H), 7.52-7.57 (m, 1H), 7.93 (br, 1H).

Step 6

To a solution of Compound (15) (4.61 g) in acetonitrile (20 ml) wereadded N,N-diisopropylethyl amine (2.42 ml) and methyl iodide (1.97 g)then the mixture was stirred at room temperature for 24 hours. Thesolvent was evaporated under reduced pressure. Water was added to theresidue and the mixture was extracted with ethyl acetate. The organiclayer was successively washed with 1 mol/L hydrochloric acid, water, asaturated aqueous solution of sodium bicarbonate, water and brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give Compound (16) (4.36 g).

¹H-NMR (CDCl₃) δ: 1.80 (s, 3H), 1.96 (s, 3H), 2.06 (s, 3H), 3.14 (s,2H), 3.74 (s, 6H), 3.80 (s, 6H), 4.52 (s, 4H), 6.40-6.49 (m, 4H), 7.00(dd, J=11.4, 8.9 Hz, 1H), 7.09-7.14 (m, 3H), 7.71-7.80 (m, 2H).

Step 7

To a solution of Compound (16) (4.36 g) in acetonitrile (20 ml) wasadded N,N-diisopropylethyl amine (3.36 ml) then the mixture was heatedunder reflux for 48 hours. Water was added to the reaction solution andthe mixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by column chromatography to giveCompound (17) (820 mg).

¹H-NMR (CDCl₃) δ: 1.54 (s, 3H), 1.76 (s, 3H), 3.76 (s, 6H), 3.79 (s,6H), 4.29 (d, J=16.2 Hz, 2H), 4.81 (d, J=16.2 Hz, 2H), 5.30 (d, J=2.5Hz, 1H), 6.43-6.47 (m, 4H), 6.98 (dd, J=11.1, 8.7 Hz, 1H), 7.14-7.18 (m,3H), 7.40-7.44 (m, 1H), 7.80-7.86 (m, 1H).

Step 8

To a solution of Compound (17) (34 mg) in methanol (1.5 ml) were addedpotassium carbonate (22.3 mg), THF (0.5 ml) and water (0.5 ml) then themixture was stirred for 20 hours at 40° C. To the reaction solution wereadded a saturated aqueous sodium bicarbonate solution and water and themixture was extracted with ethyl acetate. The organic layer wassuccessively washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by column chromatography to giveCompound (18) (20.7 mg).

¹H-NMR (CDCl₃) δ: 1.52 (s, 3H), 1.73 (s, 3H), 3.19 (br, 2H), 3.76 (s,6H), 3.80 (s, 6H), 4.31 (d, J=16.3 Hz, 2H), 4.81 (d, J=16.3 Hz, 2H),5.27 (d, J=2.2 Hz, 1H), 6.34-6.39 (m, 1H), 6.44-6.50 (m, 4H), 6.60 (dd,J=6.7, 3.0 Hz, 1H), 6.71 (dd, J=11.6, 8.6 Hz, 1H), 7.19 (d, J=7.9 Hz,2H).

Step 9

To a solution of Compound (18) (86.3 mg) in DMF (1 ml) were added5-cyano picolinic acid hydrate and EDC hydrochloride (40.2 mg) then themixture was stirred at room temperature for 20 hours. To the mixturewere added 5-cyano picolinic acid hydrate (53.5 mg) and EDChydrochloride (61.8 mg) and the mixture was stirred at room temperaturefor 3 hours. To the reaction solution were added a saturated aqueoussodium bicarbonate solution and water and the mixture was extracted withethyl acetate. The organic layer was successively washed with water andbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was purifiedby column chromatography to give Compound (19) (98.5 mg).

¹H-NMR (CDCl₃) δ: 1.58 (s, 3H), 1.76 (s, 3H), 3.71 (s, 6H), 3.77 (s,6H), 4.36 (d, J=16.1 Hz, 2H), 4.78 (d, J=16.1 Hz, 2H), 5.33 (d, J=3.4Hz, 1H), 6.42-6.46 (m, 4H), 7.02 (dd, J=11.2, 8.7 Hz, 1H), 7.19-7.25 (m,2H), 7.41 (dd, J=6.7, 2.9 Hz, 1H), 8.05-8.11 (m, 1H), 8.18 (dd, J=8.2,2.0 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 9.50 (brs,1H).

Step 10

To Compound (19) (98.5 mg) were added anisole (0.11 ml) andtrifluoroacetic acid (10 ml) and the mixture was stirred at 80° C. for15 hours. The solvent was evaporated under reduced pressure. To theresidue were added a saturated aqueous sodium bicarbonate solution andwater and the mixture was extracted with chloroform. The organic layerwas dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The obtained residue was purified bycolumn chromatography to give Compound (I-54) (25.9 mg).

¹H-NMR (CDCl₃) δ: 1.61 (s, 3H), 1.80 (s, 3H), 4.38 (br, 2H), 5.27 (dd,J=2.8, 1.3 Hz, 1H), 7.03 (dd, J=11.4, 8.9 Hz, 1H), 7.67 (dd, J=6.9, 2.9Hz, 1H), 7.86-7.92 (m, 1H), 8.17 (dd, J=8.1, 2.0 Hz, 1H), 8.39 (d, J=8.1Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 9.81 (brs, 1H).

Example 4 Synthesis of Compound (I-55)

Step 1

Compound (20) (30 g) was dissolved in chloroform (60 ml). To thesolution were added triethyl aluminium (33.3 g) and bromide (12.9 ml) at0° C. and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was warmed to 50° C. and stirred for 2 hours. To thereaction mixture was added trimethyl aluminium (16.0 g) and the mixturewas stirred for 1 hour. After the reaction solution was allowed to coolto room temperature, sodium acetate was added and the mixture wasfiltered through Celite. The filtrate was extracted with chloroform anddried over sodium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by chromatography to giveCompound (21) (40 g).

¹H-NMR (CDCl₃) δ: 2.56 (s, 3H), 7.53 (d, J=1.4 Hz, 1H), 7.58 (d, J=1.4Hz, 1H).

Step 2

Compound (21) (27 g) was dissolved in tetrahydrofuran (150 ml). To thesolution were added (R)-2-methyl propane-2-sulfinamide (20 g) andtitanium tetraethoxide (38.6 ml) and the mixture was stirred at 70° C.for 3.5 hours, followed by stirring for 6 hours at 90° C. To thereaction mixture was added brine and filtered through Celite. Thefiltrate was extracted with ethyl acetate and dried over sodium sulfate.The solvent was evaporated under reduced pressure and the obtainedresidue was purified by chromatography to give Compound (22) (30.1 g).

¹H-NMR (CDCl₃) δ: 1.30 (s, 9H), 2.71 (s, 3H), 7.39 (d, J=1.4 Hz, 1H),7.41 (d, J=1.4 Hz, 1H).

Step 3

To tetrahydrofuran (70 ml) in a eggplant flask were added lithiumdiisopropyl amide (100 ml, 2 M), t-butyl acetate (26.4 ml) andtriisopropoxy titanium (Iv) chloride (98 ml) at −70 to −60° C. and themixture was stirred for 1 hour. To the reaction mixture were addedCompound (22) (30.1 g) and tetrahydrofuran (98 ml) and the mixture wasstirred at −60 to −50° C. for 1.5 hours. A saturated aqueous solution ofammonium chloride was added to the reaction mixture. The mixture wasfiltered through Celite and the filtrate was dried over sodium sulfate.The solvent was evaporated under reduced pressure and the obtainedresidue was purified by chromatography to give Compound (23) (13.4 g).

¹H-NMR (CDCl₃) δ: 1.29 (s, 9H), 1.37 (s, 9H), 1.79 (s, 3H), 2.89 (d,J=15.8 Hz, 1H), 2.99 (d, J=15.8 Hz, 1H), 5.74 (s, 1H), 6.81 (d, J=1.4Hz, 1H), 7.09 (d, J=1.4 Hz, 1H).

Step 4

Compound (23) (13.4 g) was dissolved in toluene (50 ml) and was addedDIBAL (58 ml, 1M in hexane) at −78° C. After the mixture was stirred at0° C. for 2 hours, ethyl acetate and an aqueous solution of Rochellesalt were added and the mixture was extracted. The oil layer was washedwith water and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was purified bychromatography and recrystallized to give Compound (24) (2.62 g).

¹H-NMR (CDCl₃) δ: 1.27 (s, 9H), 1.78 (s, 3H), 2.17 (ddd, J=15.1, 6.1,3.4 Hz, 1H), 2.30 (brddd, J=15.1, 8.5, 3.4 Hz, 1H), 3.15 (brdd, J=7.5,3.4 Hz, 1H), 3.74 (dddd, J=11.8, 8.5, 7.5, 3.4 Hz, 1H), 3.95 (dddd,J=11.8, 6.1, 3.4, 3.4 Hz, 1H), 5.20 (brs, 1H), 6.77 (d, J=1.4 Hz, 1H),7.11 (d, J=1.4 Hz, 1H).

Step 5

Compound (24) (1.0 g) was dissolved in methanol (10 ml). To the solutionwas added concentrated hydrochloric acid (2 ml) at 0° C. The mixture wasstirred for 1 hour at 0° C. followed by stirring at room temperature for2 hours. To the reaction solution were added a saturated aqueous sodiumbicarbonate solution and ethyl acetate and the mixture was extracted anddried over sodium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by chromatography to giveCompound (25) (617 mg).

¹H-NMR (CDCl₃) δ: 1.60 (s, 3H), 1.94 (ddd, J=14.4, 6.5, 4.4 Hz, 1H),1.97 (ddd, J=14.4, 6.8, 4.4 Hz, 1H), 2.47 (brs, 2H), 3.67 (ddd, J=11.5,6.5, 4.4 Hz, 1H), 3.82 (ddd, J=11.5, 6.8, 4.4 Hz, 1H), 6.83 (d, J=1.4Hz, 1H), 7.09 (d, J=1.4 Hz, 1H).

Step 6

Compound (25) (200 mg) was dissolved in tetrahydrofuran (2 ml). To thesolution was added benzoyl isothiocyanate (121 μl) and the mixture wasstirred for 30 minutes. The solvent was evaporated under reducedpressure to give Compound (26) (280 mg, quant).

¹H-NMR (CDCl₃) δ: 2.07 (s, 3H), 2.33 (dt, J=13.5, 6.3 Hz, 1H), 2.71 (dt,J=13.5, 6.3 Hz, 1H), 3.82 (dt, J=11.2, 6.3 Hz, 1H), 3.84 (dt, J=11.2,6.3 Hz, 1H), 6.90 (brs, 1H), 7.13 (brs, 1H), 7.51 (m, 2H), 7.63 (m, 1H),7.84 (m, 2H), 8.84 (s, 1H), 11.46 (s, 1H).

Step 7

Compound (26) (280 mg) was dissolved in dichloromethane (4 ml). To thesolution was added mCPBA (514 mg) at room temperature and the mixturewas stirred at room temperature for 1 hour. To the mixture were added asaturated aqueous sodium bicarbonate solution and ethyl acetate and themixture was extracted and dried over sodium sulfate. The insoluble solidin dichloromethane was removed by filtration and the solvent wasevaporated under reduced pressure to give Compound (27) (340 mg, quant).

¹H-NMR (CDCl₃) δ: 1.83 (s, 3H), 2.32 (dd, J=5.8, 4.0 Hz, 1H), 2.33 (dd,J=8.1, 4.0 Hz, 1H), 4.28 (ddd, J=11.8, 8.1, 5.8 Hz, 1H), 4.45 (ddd,J=11.8, 4.0, 4.0 Hz, 1H), 6.92 (d, J=1.4 Hz, 1H), 7.18 (d, J=1.4 Hz,1H), 7.42 (m, 2H), 7.50 (m, 1H), 8.22 (m, 2H).

Step 8

Compound (27) (340 mg) was dissolved in ethanol (4 ml). To the solutionwas added sodium hydroxide (320 mg) and stirred at 90° C. for 2.5 hours.The reaction mixture was made acidified with 2 mol/L aqueous solution ofhydrochloric acid. The solution was back-extracted with ethyl acetate toremove an impure material. The aqueous layer was alkalinized with sodiumcarbonate and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and the solvent was evaporated under reducedpressure to give Compound (28) (141 mg).

¹H-NMR (CDCl₃) δ: 1.54 (s, 3H), 2.04 (ddd, J=13.9, 8.9, 4.6 Hz, 1H),2.07 (ddd, J=13.9, 4.6, 4.2 Hz, 1H), 4.01 (ddd, J=10.9, 8.9, 4.2 Hz,1H), 4.16 (ddd, J=10.9, 4.6, 4.6 Hz, 1H), 6.74 (d, J=1.4 Hz, 1H), 7.05(d, J=1.4 Hz, 1H).

Step 9

Compound (28) (141 mg), Compound (29) (149 mg), palladium (0) tetrakistriphenylphosphine complex (118 mg) and sodium carbonate (217 mg) wasadded in a eggplant flask. After nitrogen gas replacement was carriedout, dioxane (5 ml) and water (0.2 ml) were added and the mixture wasstirred at 110° C. for 7 hours. After the reaction mixture was allowedto cool to room temperature, the mixture was acidified with water and 2mol/L aqueous solution of hydrochloric acid. The solution wasback-extracted with ethyl acetate to remove an impure material. Theaqueous layer was alkalinized with potassium carbonate and extractedwith ethyl acetate. The organic layer was filtered through Celite anddried over sodium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by chromatography andrecrystallized to give Compound (I-55) (11.5 mg).

The following compounds are prepared in a similar manner to the above.In the tables, RT means retention time (minute) and D means deuterium.

TABLE 1-1 MS LC/MS No. Structure NMR (solvent: shift value ascendingorder) [M + 1] RT I-1

1H-NMR (DMSO-d6) δ: 1.55 (3H, s), 2.72 (1H, d, 14.4 Hz), 2.81 (1H, d,14.4 Hz), 4.14 (2H, br), 4.20 (1H, s), 4.53 (1H, s), 7.06 (1H, dd, J =11.5, 9.0 Hz), 7.71 (1H, dd, J = 6.9, 3.0 Hz), 7.96 (1H, ddd, J = 9.0,4.2, 3.0 Hz), 8.19 (1H, dd, J = 8.1, 1.8 Hz), 8.42 (1H, d, J = 8.1 Hz),8.88 (1H, d, J = 1.8 Hz), 9.85 (1H, s) I-2

1H-NMR (CDCl3) δ: 1.54 (3H, s), 2.71 (1H, d, J = 14.4 Hz), 2.80 (1H, d,J = 14.4 Hz), 4.15 (2H, br), 4.19 (1H, d, J = 0.9 Hz), 4.52 (1H, d, J =0.9 Hz), 7.04 (1H, dd, J = 11.7, 8.8 Hz), 7.65 (1H, dd, J = 6.9, 2.9Hz), 7.87 (1H, dd, J = 8.4, 2.4 Hz), 7.98 (1H, ddd, J = 8.8, 4.2, 2.9Hz), 8.23 (1H, d, J = 8.4, 0.6 Hz), 8.55 (1H, d, J = 2.4, 0.6 Hz), 9.82(1H, s) 375, 377 1.27 I-3

1H-NMR (CDCl3) δ: 1.54 (3H, s), 2.71 (1H, d, J = 14.2 Hz), 2.80 (1H, d,J = 14.2 Hz), 4.06 (3H, s), 4.16 (2H, br), 4.19 (1H, d, J = 0.9 Hz),4.52 (1H, d, J = 0.9 Hz), 7.03 (1H, dd, J = 11.6, 8.8 Hz), 7.62 (1H, dd,J = 7.0, 2.8 Hz), 7.97 (1H, ddd, J = 8.8, 4.0, 2.8 Hz), 8.13 (1H, d, J =1.4 Hz), 9.00 (1H, d, J = 1.4 Hz), 9.49 (1H, s) 372 1.13 I-4

1H-NMR (CDCl3) δ: 1.53 (3H, s), 2.71 (1H, d, J = 14.1 Hz), 2.81 (1H, d,J = 14.1 Hz), 4.18 (2H, br), 4.20 (1H, s), 4.53 (1H, s), 7.03 (1H, dd, J= 11.6, 8.8 Hz), 7.56 (1H, dd, J = 6.9, 2.6 Hz), 7.89 (1H, J = 2.1 Hz),8.03 (1H, ddd, J = 8.8, 4.0, 2.6 Hz), 8.44 (1H, d, J = 2.1 Hz), 9.72(1H, s) 409, 411 1.26 I-5

1H-NMR (CDCl3) δ: 1.54 (3H, d, J = 0.9 Hz), 2.71 (1H, d, J = 14.4 Hz),2.80 (1H, d, J = 14.4 Hz), 4.15 (2H, br), 4.20 (1H, d, J = 1.5 Hz), 4.52(1H, d, J = 15 Hz), 7.03 (1H, dd, J = 11.6, 8.8 Hz), 7.38 (1H, ddd, J =10.2, 8.4, 2.1 Hz), 7.59 (1H, dd, J = 6.9, 2.8 Hz), 8.00 (1H, ddd, J =8.8, 4.0, 2.8 Hz), 8.34 (1H, d, J = 2.1 Hz), 9.59 (1H, s) 377 1.12 I-6

1H-NMR (CDCl3) δ: 1.59 (3H, d, J = 1.2 Hz), 2.14 (1H, ddd, J = 13.8,9.6, 4.0 Hz), 2.38 (1H, ddd, J = 13.8, 5.4, 3.3 Hz), 3.89 (1H, ddd, J =10.9, 9.6, 3.3 Hz), 4.19 (1H, ddd, J = 10.9, 5.4, 4.0 Hz), 7.06 (1H, dd,J = 11.5, 8.8 Hz), 7.56 (1H, dd, J = 7.0, 2.8 Hz), 8.03 (1H, ddd, J =8.8, 4.0, 2.8 Hz), 8.19 (1H, dd, J = 8.2, 2.0 Hz), 8.42 (1H, dd, J =8.2, 0.8 Hz), 8.89 (1H, dd, J = 2.0, 0.8 Hz), 9.86 (1H, s)

TABLE 1-2 MS LC/MS No. Structure NMR (solvent: shift value ascendingorder) [M + 1] RT I-7

1H-NMR (CDCl3) δ: 1.70 (3H, s), 2.14 (1H, ddd, J = 13.8, 9.6, 4.0 Hz),2.68 (1H, ddd, J = 14.2, 6.0, 3.4 Hz), 3.84 (1H, ddd, J = 11.6, 8.3, 2.5Hz), 4.15 (1H, ddd, J = 10.9, 6.1, 4.0 Hz), 7.38 (1H, d, J = 8.6 Hz),7.77 (1H, d, J = 2.7 Hz), 8.01 (1H, dd, J = 8.6, 2.7 Hz), 8.19 (1H, dd,J = 8.1, 2.0 Hz), 8.42 (1H, dd, J = 8.1, 0.8 Hz), 8.89 (1H, dd, J = 2.0,0.8 Hz), 9.89 (1H, s) I-8

1H-NMR (CDCl3) δ: 1.59 (3H, d, J = 1.1 Hz), 2.12 (1H, ddd, J = 13.8,9.6, 3.9 Hz), 2.36 (1H, ddd, J = 13.8, 5.4, 3.3 Hz), 3.87 (1H, ddd, J =10.9, 9.6, 3.3 Hz), 4.17 (1H, ddd, J = 10.9, 5.4, 3.9 Hz), 7.04 (1H, dd,J = 11.6, 8.7 Hz), 7.52 (1H, dd, J = 6.9, 2.9 Hz), 7.87 (1H, dd, J =8.4, 2.4 Hz), 8.03 (1H, ddd, J = 8.7, 4.1, 2.9 Hz), 8.23 (1H, d, J =8.4, 0.8 Hz), 8.55 (1H, d, J = 2.4, 0.8 Hz), 9.82 (1H, s) 363, 365 1.15I-9

1H-NMR (CDCl3) δ: 1.58 (3H, d, J = 1.1 Hz), 2.12 (1H, ddd, J = 14.4,9.6, 3.9 Hz), 2.35 (1H, ddd, J = 14.4, 5.4, 3.3 Hz), 3.87 (1H, ddd, J =11.1, 9.6, 3.3 Hz), 4.15 (1H, ddd, J = 11.1, 5.4, 3.9 Hz), 7.03 (1H, dd,J = 11.4, 8.9 Hz), 7.40 (1H, dd, J = 6.9, 2.9 Hz), 7.89 (1H, d, J = 2.1Hz), 8.10 (1H, ddd, J = 8.9, 4.1, 2.9 Hz), 8.47 (1H, d, J = 2.1 Hz),9.72 (1H, s) 397, 399 1.19 I-10

1H-NMR (CDCl3) δ: 1.60 (3H, d, J = 1.2 Hz), 2.12 (1H, ddd, J = 13.8,9.6, 3.9 Hz), 2.36 (1H, ddd, J = 13.8, 5.4, 3.3 Hz), 3.87 (1H, ddd, J =10.8, 9.6, 3.3 Hz), 4.06 (3H, s), 4.17 (1H, ddd, J = 10.8, 5.4, 3.9 Hz),7.04 (1H, dd, J = 11.7, 8.9 Hz), 7.48 (1H, dd, J = 7.2, 2.8 Hz), 8.03(1H, ddd, J = 8.9, 4.2, 2.8 Hz), 8.15 (1H, d, J = 1.3 Hz), 9.00 (1H, d,J = 1.3 Hz), 9.50 (1H, s) 360 1.06 I-11

1H-NMR (CDCl3) δ: 1.62 (3H, d, J = 1.2 Hz), 2.14 (1H, ddd, J = 14.1,9.9, 4.2 Hz), 2.39 (1H, ddd, J = 14.1, 5.4, 3.0 Hz), 3.90 (1H, ddd, J =11.1, 9.9, 3.0 Hz), 4.19 (1H, ddd, J = 11.1, 5.4, 4.2 Hz), 7.05 (1H, dd,J = 11.6, 8.7 Hz), 7.38 (1H, ddd, J = 10.2, 8.4, 2.1 Hz), 7.45 (1H, dd,J = 7.0, 2.8 Hz), 8.07 (1H, ddd, J = 8.7, 4.1, 2.8 Hz), 8.36 (1H, d, J =2.1 Hz), 9.61 (1H, s) 365 1.00

TABLE 1-3 No. Structure NMR (solvent: shift value ascending order) I-12

¹H-NMR (CDCl₃) δ: 1.58 (3H, s), 2.22 (2H, t, J = 5.4 Hz), 3.86-3.94 (1H,m), 4.15-4.25 (3H, m), 7.14 (1H, dd, J = 10.7, 8.9 Hz), 8.09- 8.15 (1H,m), 8.62 (1H, dd, J = 7.0, 3.0 Hz). I-13

¹H-NMR (CDCl₃) δ: 1.54 (3H, s), 1.97-2.07 (1H, m), 2.30-2.38 (1H, m),3.54 (2H, brs), 3.83 (1H, dt, J = 3.2, 10.6 Hz), 4.10 (1H, ddd, 10.6,4.7, 4.2 Hz), 6.48 (1H, ddd, 8.4, 3.7, 3.2 Hz), 6.78 (1H, dd, J = 11.8,8.4 Hz), 6.86 (1H, dd, J = 6.9, 3.0 Hz). I-14

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.54 (9H, s), 1.75 (3H, s), 2.70 (1H, d,J = 14.0 Hz), 3.20 (1H, d, J = 14.0 Hz), 4.25 (1H, s), 4.66 (1H, s),6.48 (1H, s), 6.96 (1H, br), 7.02 (1H, dd, J = 11.4, 9.0 Hz), 7.51 (1H,m), 10.0 (1H, s). I-15

¹H-NMR (CDCl₃) δ: 1.63 (3H, s), 2.69 (1H, d, J = 14.1 Hz), 3.02 (1H, d,J = 14.1 Hz), 3.58 (2H, s), 4.28 (1H, s), 4.60 (1H, s), 6.51 (1H, ddd, J= 8.8, 3.2, 2.8 Hz), 6.72 (1H, dd, J = 6.9, 2.8 Hz), 6.81 (1H, dd, J =11.7, 8.8 Hz). I-16

I-17

I-18

I-19

TABLE 1-4 No. Structure I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

TABLE 1-5 No. Structure I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

TABLE 1-6 MS LC/MS No. Structure NMR (solvent: shift value ascendingorder) [M + 1] RT I-52

1H-NMR (CDCl3) δ: 2.37-2.46 (2H, m). 3.91 (1H, td, J = 9.9, 3.9 Hz),4.21-4.31 (3H, m), 6.06 (1H, t, J = 56.1 Hz), 7.12 (1H, dd, J = 11.4,8.9 Hz), 7.70 (1H, J = 6.9, 2.8 Hz), 8.13 (1H, ddd, J = 8.9, 4.2, 2.8Hz), 8.20 (1H, dd, J = 8.1, 2.1 Hz), 8.42 (1H, dd, J = 8.14, 0.9 Hz),8.89 (1H, dd, J = 2.1, 0.9 Hz), 9.89 (1H, s) 390 0.96 I-53

1H-NMR (CDCl3) δ: 2.33-2.46 (2H, m). 3.91 (1H, td, J = 10.5, 4.2 Hz),4.21-4.30 (3H, m), 6.06 (1H, t, J = 56.1 Hz), 7.11 (1H, dd, J = 11.4,8.9 Hz), 7.70 (1H, J = 6.9, 2.7 Hz), 8.12 (1H, ddd, J = 8.9, 3.9, 2.7Hz), 8.20 (1H, dd, J = 8.1, 1.8 Hz), 8.42 (1H, d, J = 8.1 Hz), 8.89 (1H,d, J = 1.8 Hz), 9.89 (1H, s) I-54

1H-NMR (CDCl3) δ: 1.61 (s, 3H), 1.80 (s, 3H), 4.38 (br, 2H), 5.27 (dd, J= 2.8, 1.3 Hz, 1H), 7.03 (dd, J = 11.4, 8.9 Hz, 1H), 7.67 (dd, J = 6.9,2.9 Hz, 1H), 7.86-7.92 (m, 1H), 8.17 (dd, J = 8.1, 2.0 Hz, 1H), 8.39 (d,J = 8.1 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 9.81 (brs, 1H). 366 0.99 I-55

1H-NMR (CDCl3) δ: 1.63 (s, 3H), 2.09 (s, 3H), 2.11 (ddd, J = 13.8, 9.7,4.5 Hz, 1H), 2.17 (ddd, J = 13.8, 4.5, 3.7 Hz, 1H), 4.08 (ddd, J = 10.6,9.7, 3.7 Hz, 1H), 4.21 (ddd, J = 10.6, 4.5, 4.5 Hz, 1H), 7.10 (d, J =1.4 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 7.82 (dd, J = 2.1, 1.8 Hz, 1H),8.49 (d, J = 1.8 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H). 311 1.01 I-56

1H-NMR (CDCl3) δ: 1.60 (3H, d, J = 0.9 Hz), 1.79 (3H, d, J = 0.9 Hz),5.24-5.25 (1H, m), 7.02 (1H, dd, J = 11.4, 8.8 Hz), 7.37 (1H, ddd, J =10.5, 8.1, 2.1 Hz), 7.53 (1H, dd, J = 6.9, 2.9 Hz), 7.93 (1H, ddd, J =8.8, 4.2, 2.9 Hz), 8.33 (1H, d, J = 2.1 Hz), 9.57 (1H, s). 377 1.09 I-57

1H-NMR (CDCl3) δ: 1.61 (3H, d, J = 0.9 Hz), 1.80 (3H, d, J = 0.9 Hz),4.16 (2H, br s), 5.24-5.26 (1H, m), 7.03 (1H, dd, J = 11.3, 8.7 Hz),7.61 (1H, dd, J = 7.0, 2.7 Hz), 7.84- 7.92 (2H, m), 8.23 (1H, d, J = 8.4Hz), 8.54 (1H, d, J = 2.1 Hz), 9.80 (1H, s). 375 1.2 

TABLE 1-7 MS LC/MS No. Structure NMR (solvent: shift value ascendingorder) [M + 1] RT I-58

1H-NMR (CDCl3) δ: 1.62 (3H, d, J = 1.2 Hz), 1.80 (3H, d, J = 1.1 Hz),5.26-5.28 (1H, m), 7.03 (1H, dd, J = 11.4, 8.8 Hz), 7.64 (1H, dd, J =6.9, 2.8 Hz), 7.91 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.14 (1H, dd, J =8.2, 1.6 Hz), 8.40 (1H, d, J = 8.2 Hz), 8.84-8.85 (1H, m), 9.90 (1H, s).409 1.32 I-59

1H-NMR (CDCl3) δ: 1.60 (3H, d, J = 0.9 Hz), 1.79 (3H, d, J = 1.1 Hz),4.06 (3H, s), 5.24-5.25 (1H, m), 7.02 (1H, dd, J = 11.4, 8.8 Hz), 7.57(1H, dd, J = 6.9, 2.9 Hz), 7.89 (1H, ddd, J = 8.8, 4.1, 2.9 Hz), 8.12(1H, d, J = 1.2 Hz), 8.99 (1H, d, J = 1.2 Hz), 9.47 (1H, s). 372 1.07I-60

1H-NMR (CDCl3) δ: 1.61 (3H, s), 1.80 (3H, s), 5.26 (1H, d, J = 1.1 Hz),7.04 (1H, dd, J = 11.2, 8.8 Hz), 7.55 (1H, dd, J = 6.8, 2.8 Hz),7.87-7.95 (2H, m), 8.68-8.68 (1H, m), 9.62 (1H, s). 384 1.07 I-61

1H-NMR (CDCl3) δ: 1.61 (3H, s), 1.80 (3H, s), 5.26-5.27 (1H, m), 7.03(1H, dd, J = 11.2, 8.8 Hz), 7.53 (1H, dd, J = 6.7, 2.4 Hz), 7.94 (1H,ddd, J = 8.8, 3.6, 2.4 Hz), 8.14-8.15 (1H, m), 8.73 (1H, d, J = 1.7 Hz),9.68 (1H, br s). 400 1.15 I-62

1H-NMR (CDCl3) δ: 1.67 (3H, s), 1.82 (3H, s), 5.27-5.28 (1H, m), 5.68(2H, br s), 7.00 (1H, dd, J = 11.3, 8.8 Hz), 7.44 (1H, d, J = 0.9 Hz),7.52 (1H, dd, J = 7.0, 2.6 Hz), 7.77 (1H, ddd, J = 8.8, 3.6, 2.6 Hz),9.50 (1H, s). 390 1.25 I-63

1H-NMR (CDCl3) δ: 1.60 (3H, s), 1.79 (3H, s), 5.25 (1H, d, J = 1.1 Hz),7.03 (1H, dd, J = 11.3, 8.8 Hz), 7.50 (0H, t, J = 71.0 Hz), 7.59 (1H,dd, J = 6.8, 2.9 Hz), 7.87 (1H, ddd, J = 8.8, 3.9, 2.9 Hz), 8.30 (1H, d,J = 1.1 Hz), 9.04 (1H, d, J = 0.9 Hz), 9.44 (1H, s). 407 1.27

TABLE 1-8 MS LC/MS No. Structure NMR (solvent: shift value ascendingorder) [M + 1] RT I-64

1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.75 (3H, s), 5.14 (1H, d, J = 1.5Hz), 5.70-5.75 (2H, m), 7.04 (1H, dd, J = 11.7, 9.1 Hz), 7.62-7.70 (2H,m), 7.79 (1H, d, J = 7.6 Hz), 8.24 (1H, s), 9.85 (1H, s). 358 0.84 I-65

1H-NMR (CDCl3) δ: 1.63 (3H, d, J = 0.9 Hz), 1.81 (3H, d, J = 1.1 Hz),5.28-5.29 (1H, m), 6.54 (2H, br s), 7.01 (1H, dd, J = 11.3, 9.3 Hz),7.29 (1H, d, J = 1.7 Hz), 7.65-7.69 (2H, m), 8.03 (1H, d, J = 1.7 Hz),9.89 (1H, s). 381 1.24 I-66

1H-NMR (CDCl3) δ: 1.68 (3H, s), 1.83 (3H, s), 3.93 (3H, s), 4.64 (2H, brs), 5.29 (1H, d, J = 4.3 Hz), 7.00 (1H, dd, J = 11.4, 8.8 Hz), 7.51 (1H,dd, J = 7.0, 3.0 Hz), 7.78 (1H, ddd, J = 8.8, 4.0, 3.0 Hz), 9.50 (1H,s). 387 1.22 I-67

1H-NMR (CDCl3) δ: 1.61 (3H, d, J = 1.2 Hz), 1.79 (3H, d, J = 1.1 Hz),2.68 (3H, s), 5.25 (1H, dd, J = 2.7, 1.1 Hz), 7.03 (1H, dd, J = 11.3,8.8 Hz), 7.60 (1H, dd, J = 6.9, 2.8 Hz), 7.90 (1H, ddd, J = 8.8, 4.1,2.8 Hz), 8.41 (1H, d, J = 1.1 Hz), 9.34 (1H, d, J = 1.4 Hz), 9.60 (1H,s). 356 0.96

The effect of the present compound is confirmed by the following testExamples.

Test Example 1 Assay of BACE1 Inhibiting Activity

48.5 μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu:X=ε-amino-n-capronic acid, Eu=Europium cryptate) was added to each wellof 96-hole half-area plate (a black plate: Costar), and after additionof 0.5 μl of the test compound (dissolved in N,N′-dimethyl formaldehyde)and 1 μl of Recombinant human BACE1(R&D Systems), the reaction mixturewas incubated at 30° C. for 3 hours. The substrate peptide wassynthesized by reacting Cryptate TBPCOOH mono SMP (CIS biointernational) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.).The final concentrations of the substrate peptide and Recombinant humanBACE1 were adjusted to 18 nmol/L and 7.4 nmol/L, respectively, and thereaction was performed in sodium acetate buffer (50 mmol/L sodiumacetate, pH 5.0, 0.008% Triton X-100).

After the incubation for reaction, 50 μl of 8.0 μg/ml Streptavidin-XL665(CIS bio international) dissolved in phosphate buffer (150 mmol/LK₂HPO₄—KH₂PO₄, pH 7.0, 0.008% Triton X-100, 0.8 mol/L KF) was added toeach well and left stand at 30° C. for an hour. After then, fluorescenceintensity was measured (excitation wavelength: 320 nm, measuringwavelength: 620 nm and 665 nm) using Wallac 1420 multilabel counter(Perkin Elmer life sciences). Enzymatic activity was determined fromcounting ratio of each wavelength (10,000× Count 665/Count 620) and 50%inhibitory concentration against the enzymatic activity was calculated.

Compound I-1: IC₅₀ 0.0473 μmol/L

Compound I-2: IC₅₀ 0.027 μmol/L

Compound I-6: IC₅₀ 0.054 μmol/L

Compound I-53: IC₅₀ 0.046 μmol/L

Compound I-54: IC₅₀ 0.097 μmol/L

Compounds I-3, 4 and 5, 7 to 11, 52 and 55 to 60 showed the IC₅₀ valueof 30 μmol/L or less.

Test Example 2 Measurement of β-Amyloid (Aβ) Production InhibitoryEffect in Cell

Neuroblastoma SH-SY5Y cells (SH/APPwt) with human wild-type β-APPexcessively expressed therein were prepared at 8×105 cells/mL, and 150μl portions thereof were inoculated into each well of a 96-well cultureplate (Falcon). The cells were cultured for 2 hours at 37° C. in a 5%gaseous carbon dioxide incubator. Then, a solution which had beenpreliminarily prepared by adding and suspending the test compound (DMSO(dimethyl sulfoxide) solution) so as to be 2 μl/50 μl medium was addedto the cell sap. Namely, the final DMSO concentration was 1%, and theamount of the cell culture was 200 μl. After the incubation wasperformed for 24 hours from the addition of the test compound, 100 μl ofthe culture supernatant was collected from each fraction. The amount ofthe Aβ in each fraction was measured.

The Aβ amount was measured as follows. 10 μl of a homogeneous timeresolved fluorescence (HTRF) measurement reagent (Amyloid β 1-40peptide; IBA Molecular Holding, S.A.) and 10 μl of the culturesupernatant were put into a 384-well half area microplate (blackmicroplate, Costar) and mixed with each other, and then left standingovernight at 4° C. while the light was shielded. Then, the fluorescenceintensity (excitation wavelength: 337 nm, measurement wavelength: 620 nmand 665 nm) was measured with a Wallac 1420 multilabel counter (PerkinElmer life sciences). The Aβ amount was determined from the count rateat each measurement wavelength (10000× Count 665/Count 620), and theamount needed to inhibit Aβ production by 50% (IC₅₀) was calculated fromat least six different dosages.

Compound I-1: IC₅₀ 0.0155 μmol/L

Test Example 3 Lowering Effect on Brain β Amyloid in Rats

A test compound is suspended in 0.5% methylcellulose, the finalconcentration is adjusted to 2 mg/mL, and this is orally administered tomale Crj:SD rat (7 to 9 weeks old) at 10 mg/kg. In a vehicle controlgroup, only 0.5% methylcellulose is administered, and an administrationtest is performed at 3 to 8 animals per group. A brain is isolated 3hours after administration, a cerebral hemisphere is isolated, a weightthereof is measured, the hemisphere is rapidly frozen in liquidnitrogen, and stored at −80° C. until extraction date. The frozencerebral hemisphere is transferred to a homogenizer manufactured byTeflon (registered trade name) under ice cooling, a 5-fold volume of aweight of an extraction buffer (containing 1% CHAPS({3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate}), 20mmol/L Tris-HCl (pH 8.0), 150 mmol/L NaCl, Complete (Roche) proteaseinhibitor) is added, up and down movement is repeated, and this ishomogenized to solubilize for 2 minutes. The suspension is transferredto a centrifugation tube, allowed to stand on an ice for 3 hours or moreand, thereafter centrifuged at 100,000×g, 4° C. for 20 minutes. Aftercentrifugation, the supernatant is transferred to an ELISA plate(product No. 294-62501, Wako Junyaku Kogyo) for measuring β amyloid 40.ELISA measurement is performed according to the attached instruction.The lowering effect is calculated as a ratio compared to the brain βamyloid 40 level of vehicle control group of each test.

Test Example 4 CYP3A4 Fluorescent MBI Test

The CYP3A4 fluorescent MBI test is a test of investigating enhancementof CYP3A4 inhibition of a compound by a metabolism reaction, and thetest was performed using, as CYP3A4 enzyme expressed in Escherichia coliand employing, as an index, a reaction in which7-benzyloxytrifluoromethylchmarin (7-BFC) is debenzylated by the CYP3A4enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin (HFC)emitting fluorescent light.

The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC;pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reactiontemperature, 25° C. (room temperature); CYP3A4 content (expressed inEscherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25μmol/mL (at 10-fold dilution); test drug concentration, 0.625, 1.25,2.5, 5, 10, 20 μmol/L (six points).

An enzyme in a K-Pi buffer (pH 7.4) and a test drug solution as apre-reaction solution were added to a 96-well plate at the compositionof the pre-reaction, a part of it was transferred to another 96-wellplate so that it was 1/10 diluted by a substrate in a K-Pi buffer, NADPHas a co-factor was added to initiate a reaction as an index (withoutpreincubation) and, after a predetermined time of a reaction,acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 was added tostop the reaction. In addition, NADPH was added to a remainingpreincubation solution to initiate a preincubation (with preincubation)and, after a predetermined time of a preincubation, a part wastransferred to another plate so that it was 1/10 diluted with asubstrate and a K-Pi buffer to initiate a reaction as an index. After apredetermined time of a reaction, acetonitrile/0.5 mol/LTris(trishydroxyaminomethane)=4/1 was added to stop the reaction. Forthe plate on which each index reaction had been performed, a fluorescentvalue of 7-HFC which is a metabolite was measured with a fluorescentplate reader. (Ex=420 nm, Em=535 nm).

Addition of only DMSO which is a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solution,and IC₅₀ was calculated by reverse-presumption by a logistic model usinga concentration and an inhibition rate. When a difference between IC₅₀values is 5 μM or more, this was defined as (+), and, when thedifference is 3 μM or less, this was defined as (−).

Compound I-52: (−)

Test Example 5 CYP inhibition Test

Using commercially available pooled human hepatic microsome, andemploying, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2),tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation(CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadinehydroxylation (CYP3A4) as typical substrate metabolism reactions ofhuman main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), aninhibitory degree of each metabolite production amount by a testcompound was assessed.

The reaction conditions were as follows: substrate, 0.5 μmol/Lethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/LS-mephenyloin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 mmol/Lterfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; testdrug concentration, 1, 5, 10, 20 mmol/L (four points).

Each five kinds of substrates, human hepatic microsome, and a test drugin 50 mmol/L Hepes buffer as a reaction solution was added to a 96-wellplate at the composition as described above, NADPH, as a cofactor wasadded to initiate metabolism reactions as markers and, after theincubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v)solution was added to stop the reaction. After the centrifugation at3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in thesupernatant was quantified by a fluorescent multilabel counter andtolbutamide hydroxide (CYP2C9 metabolite), mephenyloin 4′hydroxide(CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadinealcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solutionand IC₅₀ was calculated by reverse presumption by a logistic model usinga concentration and an inhibition rate.

I-53: five kinds >20 μM

Test Example 6 FAT Test

Each 20 μL of freeze-stored Salmonella typhimurium (TA98 and TA100strain) is inoculated in 10 mL of liquid nutrient medium (2.5% Oxoidnutrient broth No. 2), and the cultures are incubated at 37° C. undershaking for 10 hours. 9 mL of TA98 culture is centrifuged (2000×g, 10minutes) to remove medium, and the bacteria is suspended in 9 mL ofMicro F buffer (K₂HPO₄: 3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SO₄: 1 g/L,trisodium citrate dihydrate: 0.25 g/L, MgSO₄. 7H₂O: 0.1 g/L), and thesuspension is added to 110 mL of Exposure medium (Micro F buffercontaining Biotin: 8 μg/mL, histidine 0.2 μg/mL, glucose: 8 mg/mL) 3.16mL of TA100 culture is added to 120 mL of Exposure medium to prepare thetest bacterial solution. 588 μL of the test bacterial solution (or mixedsolution of 498 μl of the test bacterial solution and 90 μL of the S9mix in the case with metabolic activation system) are mixed with each 12μL of the following solution: DMSO solution of the test substance (eightdose levels from maximum dose 50 mg/mL at 2-fold ratio); DMSO asnegative control; 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution aspositive control for TA98 without metabolic activation system; 0.25μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution aspositive control for TA100 without metabolic activation system; 40 μg/mLof 2-aminoanthracene DMSO solution as positive control for TA98 withmetabolic activation system; or 20 μg/mL of 2-aminoanthracene DMSOsolution as positive control for TA100 with metabolic activation system.12 μL of the solution and 588 μL of the test bacterial solution (a mixedsolution of 498 μl of the test bacterial solution and 90 μL of S9 mixwith metabolic activation condition) were mixed and incubated at 37° C.under shaking for 90 minutes. 460 μL of the bacterial solution exposedto the test substance is mixed with 23004 of Indicator medium (Micro Fbuffer containing biotin: 8 μg/mL, histidine 0.2 μg/mL, glucose: 8mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL is dispensed into 48wells per dose in the microwell plates, and is subjected to stationarycultivation at 37° C. for 3 days. A well containing the bacteria, whichhas obtained the ability of proliferation by mutation in the gene codingamino acid (histidine) synthetase, turns the color from purple to yellowdue to pH change. The mutagenicity was evaluated by counting the numberof the yellow wells among the 48 total wells per dose and comparing withthe negative control group. (−) means that mutagenicity is negative and(+) means positive.

Test Example 7 Solubility Test

The solubility of each compound is determined under 1% DMSO additionconditions. A 10 mM solution of the compound is prepared with DMSO, and6 μL of the compound solution is added to 594 μL of an artificialintestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are addedto 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach1000 mL) with a pH of 6.8. The mixture is left standing for 16 hours at25° C., and the mixture is vacuum-filtered. The filtrate is two-folddiluted with methanol/water=1/1, and the compound concentration in thefiltrate is measured with HPLC or LC/MS/MS by the absolute calibrationmethod.

Test Example 8 Metabolism Stability Test

Using a commercially available pooled human hepatic microsomes, a testcompound is reacted for a constant time, a remaining rate is calculatedby comparing a reacted sample and an unreacted sample, thereby, a degreeof metabolism in liver is assessed.

A reaction is performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 pit of the reaction solution is addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The test compound in the supernatant isquantified by LC/MS/MS, and a remaining amount of the test compoundafter the reaction is calculated, letting a compound amount at 0 minutereaction time to be 100%.

I-53: 100%

Test Example 9 hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation, effects on delayed rectifier K+ current (I_(Kr)), whichplays an important role in the ventricular repolarization process of thecompound of the present invention, is studied using HEK293 cellsexpressing human ether-a-go-go related gene (hERG) channel.

After a cell is retained at a membrane potential of −80 mV by whole cellpatch clamp method using an automated patch clamp system (PatchXpress7000A, Axon Instruments Inc.), induced by depolarization pulsestimulation at +40 mV for 2 seconds and, further, repolarization pulsestimulation at −50 mV for 2 seconds is recorded. After the generatedcurrent is stabilized, extracellular solution (NaCl: 135 mmol/L, KCl:5.4 mmol/L, NaH₂PO₄: 0.3 mmol/L, CaCl₂.2H₂O: 1.8 mmol/L, MgCl₂.6H₂O: 1mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test compound hasbeen dissolved at an objective concentration is applied to the cellunder the room temperature condition for 10 minutes. From the recordingI_(Kr), an absolute value of the tail peak current is measured based onthe current value at the resting membrane potential using an analysissoftware (DataXpress ver.1, Molecular Devices Corporation). Further, the% inhibition relative to the tail peak current before application of thetest compound is calculated, and compared with the vehicle-applied group(0.1% dimethyl sulfoxide solution) to assess influence of the testcompound on I_(Kr).

The Example 10 Powder Solubility Test

Appropriate amounts of the test substances are put into appropriatecontainers. To the respective containers are added 200 μL of JP-1 fluid(sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to reach 1000mL), 200 μL of JP-2 fluid (phosphate buffer (pH 6.8) 500 mL and water500 mL), and 200 μL of 20 mmol/L TCA (sodium taurocholate)/JP-2 fluid(TCA 1.08 g and water to reach 100 mL). In the case that the testcompound is dissolved after the addition of the test fluid, the bulkpowder is added as appropriate. The containers are sealed, and shakenfor 1 hour at 37° C. The mixtures are filtered, and 100 μL of methanolis added to each of the filtrate (100 μL) so that the filtrates aretwo-fold diluted. The dilution ratio may be changed if necessary. Thedilutions are observed for bubbles and precipitates, and then thecontainers are sealed and shaken. Quantification is performed by HPLCwith an absolute calibration method.

Test Example 11 BA Tests

Materials and methods for studies on oral absorption

(1) Animal: mice or rats

(2) Breeding conditions: mice or rats are allowed to freely take solidfeed and sterilized tap water

(3) Dose and grouping: orally or intravenously administered at apredetermined dose; grouping is as follows (Dose depends on thecompound)

Oral administration: 1 to 30 mg/kg (n=2 to 3)

Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of dosing solution: for oral administration, in asolution or a suspension state; for intravenous administration, in asolubilized state

(5) Administration method: in oral administration, forcedly administerinto ventriculus with oral probe; in intravenous administration,administer from caudal vein with a needle-equipped syringe

(6) Evaluation items: blood is collected over time, and the plasmaconcentration of drug is measured by LC/MS/MS

(7) Statistical analysis: regarding the transition of the plasmaconcentration, the area under the plasma concentration-time curve (AUC)is calculated by non-linear least squares program WinNonlin (Registeredtrade name), and the bioavailability (BA) is calculated from the AUCs ofthe oral administration group and intravenous administration group

Compound I-53: 80.4%

Test Example 12 Brain Distribution Studies

Intravenous administration is carried out to a rat by 0.5 mg/mL/kgdosage of the compound. 30 minutes later, all blood is drawn from venacava inferior under isoflurane anesthesia for death from exsanguination.Then, the brain is extracted and 20-25% of homogenate thereof isprepared with distilled water. On the other hand, the obtained blood isused as plasma after centrifuging. Then, to the brain sample is addedthe control plasma at 1:1. To the plasma samples is added the controlbrains at 1:1. Each sample is measured using LC/MS/MS. The obtained arearatio (a brain/plasma) is used for the brain Kp value.

Formulation Example 1

A granule containing the following ingredients is produced.

Ingredient Compound of the formula (I)  10 mg Lactose 700 mg Corn starch274 mg HPC-L  16 mg 1000 mg 

The compound of the formula (I), and lactose are passed through a 60mesh sieve. Corn starch is passed through a 120 mesh sieve. These aremixed with a V-type mixer. To the mixed powder is added a HPC-L (lowviscosity hydroxypropylcellulose) aqueous solution, this is kneaded,granulated (extrusion granulation, pore diameter 0.5 to 1 mm), anddried. The resulting dry granule is passed through a vibration sieve(12/60 mesh) to give a granule.

Formulation Example 2

A granule for filling a capsule containing the following ingredients isproduced.

Ingredient Compound of the formula (I) 15 mg Lactose 90 mg Corn starch42 mg HPC-L  3 mg 150 mg 

The compound of the formula (I), and lactose are passed through a 60mesh sieve. Corn starch is passed through a 120 mesh sieve. These aremixed, a HPC-L solution is added to the mixed powder, this is kneaded,granulated, and dried. The resulting dry granule is adjusted in a size,and 150 mg of it is filled into a No. 4 hard gelatin capsule.

Formulation Example 3

A tablet containing the following ingredients is produced.

Ingredient Compound of the formula (I) 10 mg Lactose 90 mgMicrocrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg150 mg 

The compound of the formula (I), lactose, microcrystalline cellulose,and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60mesh sieve, and mixed. Magnesium stearate is mixed into the mixed powderto give a mixed powder for tabletting. The present mixed powder isdirectly compressed to give a 150 mg of a tablet.

Formulation Example 4

The following ingredients are warmed, mixed, and sterilized to give aninjectable.

Ingredient Compound of the formula (I)  3 mg Nonionic surfactant 15 mg Purified water for injection 1 ml

INDUSTRIAL APPLICABILITY

The present compound can be a medicament useful as an agent for treatingor preventing a disease induced by production, secretion and/ordeposition of amyloid β protein.

The invention claimed is:
 1. A method for the treatment and/or symptom improvement of dementia of the Alzheimer's type, Down's syndrome, memory impairment, Creutzfeldt-Jakob disease, mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, mixed dementia with Alzheimer's and vascular type, dementia with Parkinson's Disease, dementia with progressive supranuclear palsy, dementia with Cortico-basal degeneration, Alzheimer's disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's Disease, or amyloid angiopathy in a subject, comprising administering a compound of formula (I):

wherein ring A is a substituted benzene or a substituted or unsubstituted thiophene, R¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R^(2a) and R^(2b) are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,

wherein R^(za) and R^(zb) are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy or substituted or unsubstituted heterocyclyloxycarbonyl, or R^(za) and R^(zb) together with the carbon atom to which they are attached may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle, R^(3a), R^(3b), R^(4a) and R^(4b) are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl or substituted or unsubstituted heterocyclylsulfonyl, R^(3a) and R^(3b) together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, R^(4a) and R^(4b) together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, dashed line a means the presence or absence of a bond, when dashed line a means the presence of a bond, then R^(3b) and R^(3b) are absent, wherein the teen “acyl” includes formyl, alkylcarbonyl of a carbon number of 1 to 10, alkenylcarbonyl of a carbon number of 2 to 10, alkynylcarbonyl of a carbon number of 2 to 10, carbocyclylcarbonyl and heterocyclylcarbonyl, the substituents of “substituted benzene”, “substituted or unsubstituted carbocycle”, “substituted or unsubstituted thiophene” and “substituted or unsubstituted heterocycle” in ring A, ring A′ and ring B are one or more substituents selected from (A) a group selected from the substituent group α wherein the substituent group α is a group consisting of halogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and a heterocyclic group, each of which carbocycle and heterocycle is optionally substituted with one or more substituent selected from halogen, alkyl, hydroxy, and alkoxy; (B) alkyl substituted with one or more groups selected from the substituent group α, hydroxyimino and alkoxyimino, or unsubstituted alkyl; (C) aminoalkyl substituted with one or more groups selected from the substituent group α; alkenyl substituted with one or more substituents selected from the substituent group α, or unsubstituted alkenyl; (D) alkynyl substituted with one or more substituents selected from the substituent group α, or unsubstituted alkynyl; (E) alkoxy substituted with one or more substituents selected from the substituent group α; (F) alkoxyalkoxy substituted with one or more substituents selected from the substituent group α; (G) alkenyloxy substituted with one or more substituents selected from the substituent group α, or unsubstituted alkenyloxy; (H) alkoxyalkenyloxy substituted with one or more substituents selected from the substituent group α; (I) alkynyloxy substituted with one or more substituents selected from the substituent group α, unsubstituted alkynyloxy; (J) alkoxyalkynyloxy substituted with one or more groups selected from the substituent group α; (K) alkylthio substituted with one or more substituents selected from the substituent group α, or unsubstituted alkylthio; (L) alkenylthio substituted with one or more substituents selected from the substituent group α, or unsubstituted alkenylthio; (M) alkynylthio substituted with one or more substituents selected from the substituent group α, or unsubstituted alkynylthio; (N) alkylamino substituted with one or more substituents selected from the substituent group α; (O) alkenylamino substituted with one or more substituents selected from the substituent group α; (P) alkynylamino substituted with one or more substituents selected from the substituent group α; (Q) aminooxy substituted with one or more substituents selected from the substituent group α and alkylidene, or unsubstituted aminooxy; (R) acyl substituted with one or more substituents selected from the substituent group α; (S) alkylsulfonyl substituted with one or more substituents selected from the substituent group α, or unsubstituted alkylsulfonyl; (T) alkylsulfinyl substituted with one or more substituents selected from the substituent group α, or unsubstituted alkylsulfinyl; (U) alkylsulfamoyl substituted with one or more substituents selected from the substituent group α; (V) a carbocyclic group substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl; (W) a heterocyclic group substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl; (X) carbocyclylalkyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylalkyl; (Y) heterocyclylalkyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylalkyl; (Z) carbocyclyloxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclyloxy; (AA) heterocyclyloxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclyloxy; (AB) carbocyclylalkoxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylalkoxy; (AC) heterocyclylalkoxy substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylalkoxy; (AD) carbocyclylalkoxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylalkoxycarbonyl; (AE) heterocyclylalkoxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylalkoxycarbonyl; (AF) carbocyclylthio such substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylthio; (AG) heterocyclylthio substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylthio; (AH) carbocyclylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylamino; (AI) heterocyclylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylamino; (AJ) carbocyclylalkylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl or unsubstituted carbocyclylalkylamino; (AK) heterocyclylalkylamino substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylalkylamino; (AL) carbocyclylsulfamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylsulfamoyl; (AM) heterocyclylsulfamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylsulfamoyl; (AN) carbocyclylsulfonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylsulfonyl; (AO) heterocyclylsulfonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylsulfonyl; (AP) carbocyclylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylcarbamoyl; (AQ) heterocyclylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylcarbamoyl; (AR) carbocyclylalkylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylalkylcarbamoyl; (AS) heterocyclylalkylcarbamoyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclylalkylcarbamoyl; (AT) carbocyclyloxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted carbocyclyloxycarbonyl; (AU) heterocyclyloxycarbonyl substituted with one or more substituents selected from the substituent group α, azide, alkyl and halogenoalkyl, or unsubstituted heterocyclyloxycarbonyl; (AV) alkylenedioxy substituted with halogen, or unsubstituted alkylenedioxy; (AW) oxo; and (AX) azide; and ring A may be selected from the followings:

wherein ring A′ and ring B are each independently substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle wherein the substituents are defined above, L¹, L², and L³ are each independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, ═W¹ is ═O, ═S, or ═NR⁹, W² is O, S, or N(R⁸), R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, R⁹ is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, when ring A is (i), then the constituent carbon atom of L¹ and the constituent carbon atom of L², or the constituent carbon atom of L¹ and the nitrogen atom of W² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (ii), then the constituent carbon atom of L¹ and the constituent carbon atom of L², or the nitrogen atom of W² and the constituent carbon atom of L² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (iii), then two nitrogen atoms of W² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (vi), then the constituent carbon atom of L¹ and the constituent carbon atom of L² may be connected by substituted or unsubstituted alkylene to form a ring, p is 1 or 2, and when multiple L³, multiple W², or multiple R⁹ are present, each of them may be independently different; the substituents of “substituted or unsubstituted alkyl”, “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkylsulfinyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkenyloxy”, “substituted or unsubstituted alkenyloxycarbonyl”, “substituted or unsubstituted alkenylthio”, “substituted or unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkynyloxy”, “substituted or unsubstituted alkynylthio”, “substituted or unsubstituted alkynyloxycarbonyl”, “substituted or unsubstituted alkynylsulfinyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted alkylene”, “substituted or unsubstituted alkenylene”, and “substituted or unsubstituted alkynylene” are one or more substituents selected from a substituent group α: the substituents of “substituted or unsubstituted acyl” and “substituted or unsubstituted acyloxy” are one or more substituents selected from the substituent group α, and the ring portions of carbocyclylcarbonyl and heterocyclylcarbonyl may be substituted with one or more substituents selected from alkyl, substituent group α, and alkyl substituted with one or more substituents selected from substituent group α; the substituent in “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted thiocarbamoyl” and “substituted or unsubstituted sulfamoyl” are one or two substituents selected from alkyl, acyl, hydroxy, alkoxy, alkoxycarbonyl, carbocyclic group and heterocyclic group; the substituents of “substituted or unsubstituted carbocyclic group”, “substituted or unsubstituted carbocyclylthio”, “substituted or unsubstituted carbocyclyloxycarbonyl”, “substituted or unsubstituted carbocyclyloxy”, “substituted or unsubstituted carbocyclylsulfinyl”, “substituted or unsubstituted carbocyclylsulfonyl”, “substituted or unsubstituted heterocyclic group”, “substituted or unsubstituted heterocyclyloxy”, “substituted or unsubstituted heterocyclylthio”, “substituted or unsubstituted heterocyclyloxycarbonyl”, “substituted or unsubstituted heterocycylsulfinyl”, “substituted or unsubstituted heterocyclylsulfonyl” in other than the ring A and ring B are one or more substituents selected from the substituent group α, unsubstituted alkyl, and alkyl substituted with one or more substituents selected from the substituent group α; the substituent of “substituted or unsubstituted non-aromatic carbocycle”, “substituted or unsubstituted non-aromatic heterocycle” and “substituted or unsubstituted carbocycle” are one or more selected from alkyl substituted with one or more selected from the substituent group α, unsubstituted alkyl and alkyl substituted with one or more substituents selected from the substituent group α; excluding the compounds wherein

and ring A is

wherein ring A′ and ring B are each independently a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is -L¹′-N(R⁸)-L²′-, L¹′ and L²′ are each independently a bond; substituted or unsubstituted alkylene wherein the substituent is one or more selected from halogen, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkyl carbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and a heterocyclic group, each of which carbocycle and heterocycle is optionally substituted by one or more substituent selected from halogen, alkyl, hydroxy and alkoxy; substituted or unsubstituted alkenylene wherein the substituent is one or more selected from halogen, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxy imino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxy alkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and a heterocyclic group, each of which carbocycle and heterocycle is optionally substituted by one or more substituent selected from halogen, alkyl, hydroxy and alkoxy; or substituted or unsubstituted alkynylene wherein the substituent is one or more selected from halogen, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, a carbocyclic group and a heterocyclic group, each of which carbocycle and heterocycle is optionally substituted by one or more substituent selected from halogen, alkyl, hydroxy and alkoxy; and R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl its pharmaceutically acceptable salt or a solvate thereof.
 2. The method according to claim 1, wherein ring A is

wherein ring A′ is substituted or unsubstituted benzene or substituted or unsubstituted thiophene, ring B is a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or -L¹-N(R⁸)-L²-, L¹ and L² are each independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl.
 3. The method according to claim 1, wherein

R^(za) and R^(zb) are each independently hydrogen, halogen or substituted or unsubstituted alkyl, and R^(4a) and R^(4b) are each independently hydrogen or substituted or unsubstituted alkyl.
 4. The method according to claim 1, wherein

wherein R^(3a), R^(3b), R^(4a) and R^(4b) are the same as defined in claim
 1. 5. The method according to claim 1, wherein

wherein R^(3a) and R^(4a) are the same as defined in claim
 1. 6. The method according to claim 2, wherein —Z— is —C(═O)N(R⁸)—.
 7. The method according to claim 2, wherein ring A′ is substituted or unsubstituted benzene, and ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine.
 8. The method according to claim 1, wherein R^(4a) and R^(4b) are both hydrogen.
 9. The method according to claim 1, wherein R¹ is C1 to C3 unsubstituted alkyl.
 10. The method according to claim 1, wherein R^(2a) and R^(2b) are both hydrogen.
 11. The method according to claim 1, wherein ring A is

wherein ring A′ is substituted or unsubstituted benzene or substituted or unsubstituted thiophene, ring B is substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, L¹, L², and L³ are each independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, ═W¹ is ═O, ═S, or ═NR⁹, W² is O, S, or N(R⁸), R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, R⁹ is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, when ring A is (i), then the constituent carbon atom of L¹ and the constituent carbon atom of L², or the constituent carbon atom of L¹ and the nitrogen atom of W² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (ii), then the constituent carbon atom of L¹ and the constituent carbon atom of L², or the nitrogen atom of W² and the constituent carbon atom of L² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (iii), then two nitrogen atoms of W² may be connected with substituted or unsubstituted alkylene to form a ring, when ring A is (vi), then the constituent carbon atom of L¹ and the constituent carbon atom of L² may be connected by substituted or unsubstituted alkylene to form a ring, p is 1 or 2, and when multiple L³, multiple W², or multiple R⁹ are present, each of them may be independently different.
 12. The method according to claim 1, wherein R¹ is substituted alkyl.
 13. The method according to claim 1, wherein ring A′ is a substituted or unsubstituted benzene or a substituted or unsubstituted thiophene wherein the substituent is chlorine.
 14. The method according to claim 2, wherein ring B is pyridine substituted by one or more substituents selected from chloro, fluoro, fluoromethyl, alkynyl, amino, and cyano.
 15. The method according to claim 2, wherein ring B is pyrazine substituted by one or more substituents selected from methyl, methoxy, fluoromethoxy, amino, and hydroxy.
 16. The method according to claim 4, wherein R^(3a) is substituted or unsubstituted alkyl and R^(ab) is hydrogen.
 17. The method according to claim 4, wherein R^(3a) is alkyl and R^(3b) is hydrogen.
 18. The method according to claim 1, wherein the formula is represented by:


19. The method according to claim 1, wherein the compound is represented by the formula (Iα):

wherein ring A is a substituted benzene or a substituted or unsubstituted thiophene, R¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, R^(2a) and R^(2b) are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,

wherein R^(za) and R^(zb) are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, or substituted or unsubstituted heterocyclyloxycarbonyl, or R^(za) and R^(zb) together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, R^(3a), R^(3b), R^(4a) and R^(4b) are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclyloxycarbonyl, substituted or unsubstituted carbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl or substituted or unsubstituted heterocyclylsulfonyl, R^(3a) and R^(3b) together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, R^(4a) and R^(4b) together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, dashed line a means the presence or absence of a bond, when dashed line a means the presence of a bond, then R^(3b) and R^(4b) are absent, excluding the compounds wherein

ring A is

wherein ring A′ and ring B are each independently a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is -L¹-N(R⁸)-L²-, L¹ and L² are each independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene; and R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, and its pharmaceutically acceptable salt or a solvate thereof.
 20. The method according to claim 19, wherein

ring A is

wherein ring A′ is substituted or unsubstituted benzene or substituted or unsubstituted thiophene, ring B is a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, Z is —C(═O)N(R⁸)—, and R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl.
 21. The method according to claim 1, wherein the method is for the treatment and/or symptom improvement of dementia of the Alzheimer's type or mild cognitive impairment (MCI).
 22. A pharmaceutical composition for the treatment and/or symptom improvement of dementia of the Alzheimer's type, Down's syndrome, memory impairment, Creutzfeldt-Jakob disease, mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, mixed dementia with Alzheimer's and vascular type, dementia with Parkinson's Disease, dementia with progressive supranuclear palsy, dementia with Cortico-basal degeneration, Alzheimer's disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's Disease, or amyloid angiopathy in a subject comprising the compound according to claim 1, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient. 